Human Reproduction Update, Vol.17, No.3 pp. 327– 346, 2011 Advanced Access publication on November 23, 2010 doi:10.1093/humupd/dmq050

Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications Pamela Stratton 1,* and Karen J. Berkley 2 1 Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health, Bldg. 10, CRC, RM 1-3140, 10 Center Dr. MSC 1109, Bethesda, MD 20892-1109 USA 2Program in Neuroscience, Florida State University, 1107 W. Call St., Tallahassee, FL 32306-4301 USA

*Correspondence address. E-mail: [email protected]

Submitted on January 12, 2010; resubmitted on June 11, 2010; accepted on September 2, 2010

table of contents

........................................................................................................................... † † † † † † † † † †

Introduction Methods Spectrum of pain and lesions Effects of current treatments on pain associated with endometriosis Neural mechanisms of pain in endometriosis Potential therapies directed at neural involvement in pain Neuroimmune and neuroendocrine factors Contributions of the reproductive organs and functions Problems with pain assessments in practice and in clinical studies Summary, conclusions and future directions

background: Many clinicians and patients believe that endometriosis-associated pain is due to the lesions. Yet causality remains an enigma, because pain symptoms attributed to endometriosis occur in women without endometriosis and because pain symptoms and severity correlate poorly with lesion characteristics. Most research and reviews focus on the lesions, not the pain. This review starts with the recognition that the experience of pain is determined by the central nervous system (CNS) and focuses on the pain symptoms. methods: Comprehensive searches of Pubmed, Medline and Embase were conducted for current basic and clinical research on chronic pelvic pain and endometriosis. The information was mutually interpreted by a basic scientist and a clinical researcher, both in the field of endometriosis. The goal was to develop new ways to conceptualize how endometriosis contributes to pain symptoms in the context of current treatments and the reproductive tract. results: Endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the CNS. This engagement provides a mechanism by which the dynamic and hormonally responsive nervous system is brought directly into play to produce a variety of individual differences in pain that can, in some women, become independent of the disease itself.

conclusions: Major advances in improving understanding and alleviating pain in endometriosis will likely occur if the focus changes from lesions to pain. In turn, how endometriosis affects the CNS would be best examined in the context of mechanisms underlying other chronic pain conditions. Key words: endometriosis / chronic pelvic pain / central nervous system sensitization / pathophysiology / neurovascular

Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2010

328

Introduction Endometriosis is an estrogen-dependent inflammatory disease that occurs in women of reproductive age, and generally becomes inactive with menopause, unless a woman uses post-menopausal hormone therapy (Goodman et al., 1989; Takayama et al., 1998; Missmer et al., 2004; Cumiskey et al., 2008). The epidemiologic association between endometriosis and chronic pelvic pain (CPP) is suggested by the observation that among women who undergo laparoscopy, endometriosis is found in one-third who undergo surgery for CPP, compared with only 5% of those who do not have infertility or CPP (Howard, 1993, 2009). CPP often debilitates women with endometriosis for years (Sinaii et al., 2007), has a high risk of emergency department visits (Gao et al., 2006), and is associated with time lost from work and significant physical and social debility (Simoens et al., 2007). Additional expenses in women with endometriosis-related pain can arise from comorbid pain conditions like painful bladder syndrome (formerly called interstitial cystitis), migraine and irritable bowel syndrome (Mirkin et al., 2007). Gynecologists and patients believe that CPP associated with endometriosis is caused by the endometriosis lesions (Fauconnier and Chapron, 2005). Establishing how the lesions do so has proved difficult. The spectrum of pains and lesions contributes to this challenge. Although analgesics, hormonal therapies and surgeries have been the mainstay of therapy, pain often returns, and return of pain is not necessarily associated with the return of lesions. A fundamental concept is that the experience of pain is due to activity in the central nervous system (CNS). Thus, the relationship between pain and endometriosis could benefit by being reconsidered in the context of the nervous system. The purpose of this review, therefore, is to summarize the translational research that has recently exploded on this issue and to identify future directions.

Methods An electronic database search (Pubmed, Medline and Embase) was performed to identify basic and clinical studies concerned with mechanisms of pain in women with endometriosis from the earliest date available, usually 1967. Mesh terms used included endometriosis, chronic pain, CPP, sensory nerve fibers, autonomic nerve fibers, sympathetic, estradiol, pelvic pain, innervation, sensitization, medical treatments including treatments by specific names, surgical treatments, including treatments by specific names and for specific sections like the reproductive tract, additional mesh terms were added. Mesh terms were used in various combinations and usually included the terms chronic pain AND endometriosis. Few studies reviewed and included in the manuscript address this relationship. Most are studies of endometriosis pathophysiology or treatment. Thus, the review is not a formal systematic literature overview, nor were quantitative analyses carried out. Instead, the authors synthesize and interpret the existing basic, clinical and translational research regarding the association between endometriosis and pain.

Spectrum of pain and lesions The constellation of pain symptoms associated with endometriosis varies from person to person. Symptoms encompass an unspecified combination of dysmenorrhea, dyspareunia and non-menstrual

Stratton and Berkley

chronic pelvic –abdominal muscle pain with the sentinel symptom being dysmenorrhea (Table I). Non-menstrual CPP may persist for much of the month or only during specific times, such as at ovulation. Some women have additional painful symptoms such as dysuria, dyschezia and other chronic musculoskeletal conditions, which may or may not be related to endometriosis. These pain symptoms and their chronicity, patterns in relation to the menstrual cycle and association with other types of visceral pain, ultimately reflect changing actions of the nervous system. Laparoscopic surgery has enabled surgical diagnosis of endometriosis by confirming the existence of lesions and transformed its surgical treatment (Kennedy et al., 2005). The appearance and location of endometriosis lesions, like the symptoms of pain, vary from person to person. On gross inspection, endometriosis is subdivided into three categories: superficial peritoneal endometriosis, deeply infiltrating endometriosis (DIE) and ovarian (cystic) endometriosis (Brosens et al., 1993; Koninckx et al., 1994; Nisolle and Donnez, 1997; Table I). Visual survey at surgery is the accepted standard, but may not accurately catalogue the location, depth and extent of lesions. Furthermore, minimal and mild disease are not necessarily histologically confirmed, which may result in misclassifying cases (Marcoux et al., 1997; Vercellini et al., 2009b). Such confirmation is important for superficial peritoneal lesions, which vary to include classic (blue – black; considered ‘diagnostic’) and non-classic or subtle (clear or red, yellowish brown, white, scar-like) lesions (Martin et al., 1989; Albee et al., 2008). Recognizing variable appearance is critical because the frequency of biopsy-proven endometriosis is similar among all single-colored lesions and highest in mixed-color lesions (Stegmann et al., 2008b; Table I). Importantly, this identification only serves to confirm the diagnosis of endometriosis, not its relationship to pain. Definitive criteria determining which, if any, endometriosis lesions cause pain symptoms are lacking. In carefully documented studies, location and extent of lesions bear little relation to location or amount of pain a woman experiences (Vercellini et al., 1996, 2007; Parazzini

Table I Spectrum of pains and endometriosis lesions. Spectrum of pains

Dysmenorrhea Dyspareunia Non-menstrual CPP Dyschesia Dysuria Musculoskeletal pain

Spectrum of lesions

Types

Visual appearance (superficial peritoneal lesions)

Superficial peritoneal Endometriomas Deeply infiltrating lesions Clear Red Brown Yellow Black – blue White Mixed color—any lesion with two or more color types

Relationship between pain and endometriosis

et al., 2001; Chapron et al., 2003; Fauconnier and Chapron, 2005). All three lesion types are associated with CPP, including those women with only minimal or mild endometriosis using the American Society for Reproductive Medicine (ASRM) classification (Fauconnier and Chapron, 2005). Endometriomas, per se, are not associated with dysmenorrhea severity (Chopin et al., 2006), and dysmenorrhea is less frequent in women with only ovarian endometriomas compared with other locations (Vercellini et al., 1996). Endometriomas, however, may be a marker for greater severity of DIE lesions (Chapron et al., 2008). DIE lesions are the only ones that are consistently associated with CPP (Fauconnier and Chapron, 2005). Non-menstrual CPP and gastrointestinal symptoms occur at a higher rate in those with bowel DIE lesions and painful defecation during menses with DIE involving the vagina (Fauconnier et al., 2002). Importantly, endometriosis is associated with a local inflammatory response and formation of adhesions, be they spontaneous de novo adhesions or adhesions reformed after surgical treatment of endometriosis (Parker et al., 2005; Parazzini et al., 2006). The role of adhesions in pain and endometriosis is poorly understood (Rapkin, 1986; Parazzini et al., 2006; Vercellini et al., 2009b; Yeung et al., 2009).

Effects of current treatments on pain associated with endometriosis Analgesics Although most acknowledge that analgesic drugs alleviate pain in some women with endometriosis (Kennedy et al., 2005; Sinaii et al., 2007), conclusive evidence is lacking (Allen et al., 2009), and detailed information about their use and effectiveness in relieving pain is largely absent from gynecologic studies (Table II). Because analgesics are the first treatments used for dysmenorrhea and because these drugs are an integral part of acute and chronic pain treatment in other conditions, further research is needed on use and effectiveness of different types of analgesics in pain relief in endometriosis.

Hormones Most treatments of endometriosis suppress ovarian function, regarding endometriosis as an estrogen-dependent disease (Kennedy et al., 2005). Combined oral contraceptives (estrogen and progestin), danazol, gestrinone, medroxyprogesterone acetate and GnRH agonists are equally effective (Prentice et al., 2000a, b; Davis et al., 2007; Selak et al., 2007; Table II). During hormonal treatment, lesions, which may be quiescent (perhaps neurologically inactive), are observed in most women on GnRH agonists and progestagens (Nisolle-Pochet et al., 1988). Persistence of lesions is proposed to explain why pain returns after medical therapy is stopped. Yet, beyond their effect on lesions, most agents suppress ovulation and alter endometrium, frequently causing amenorrhea. When ovulation and menstruation are restored, often symptoms return, suggesting that these reproductive functions play a role in symptoms independent of lesions. Osteen et al. (2005) demonstrated that eutopic endometrium of women with endometriosis has reduced progesterone action during maturation or ‘progesterone resistance’, that, in turn, may enhance

329 development of endometriosis. The rationale for use of progestogens with or without estrogens in endometriosis treatment has been their anti-angiogenic, immunomodulatory and anti-inflammatory effects, well described by Vercellini (2003a; Table II). Progestagens and combined oral contraceptives affect eutopic endometrial cellular and paracrine characteristics such that the endometrium is fundamentally altered and becomes decidualized; these changes may inhibit implantation and growth of refluxed menstrual endometrium (Vercellini et al., 2003a). Oral contraceptives when taken cyclically suppress ovulation and thin the endometrium (Grow and Iromloo, 2006), resulting in lighter menses. No one type of oral contraceptive is more effective than another, nor is there evidence that taking oral contraceptives continuously without placebo pills is superior in relieving pain to cyclic oral, percutaneous (contraceptive patch) or transvaginal (contraceptive ring) regimens (Vercellini et al., 2003c, 2009a; Table II). Oral contraceptives and progestagens are the most recommended treatment for endometriosis because of their good safety profile, low cost and tolerability (Kennedy et al., 2005). When these agents are ineffective, poorly tolerated or contraindicated, GnRH analogues, danazol or gestrinone are used, which cost more and are less well tolerated. GnRH agonists are sometimes used prior to laparoscopic diagnosis; if symptoms are relieved, some presume that the woman has endometriosis. Leuprolide acetate, for example, was effective for pain in one randomized clinical trial; importantly, women without endometriosis also had pain relief (Ling, 1999), a finding confirmed by others (Jenkins et al., 2008). Treatment with GnRH agonists can be safely administered for up to 2 years when combined with add-back hormonal therapy for bone protection (Surrey, 1999; Surrey and Hornstein, 2002), although concerns remain about use in women who have not reached peak bone mass (Divasta et al., 2007; Laufer, 2008). The levonorgestrel intrauterine system (IUD) may also be effective in improving pain symptoms (Vercellini et al., 1999, 2003b; Lockhat et al., 2004, 2005; Petta et al., 2005; Table II), but there is insufficient evidence to recommend its use (Abou-Setta et al., 2006; Varma et al., 2006). It causes decidualization of endometrial stroma, endometrial glandular atrophy with down-regulation of endometrial cell proliferation and increase in apoptotic activity (Vercellini et al., 2005). Antiprogestins may be effective in endometriosis treatment (Kettel et al., 1998; Prentice et al., 2000a), but have not had widespread use (Table II). Similarly, aromatase inhibitors have been effective in noncontrolled studies of women who have pain unresponsive to other hormone treatments (Bulun et al., 1999; Amsterdam et al., 2005). However, use of aromatase inhibitors requires ovarian suppression with another hormonal agent (Table II). A lack of relationship between lesions and CPP, and ineffectiveness of raloxifene in relieving pain symptoms were shown in a randomized, double-blind, placebo-controlled study of raloxifene taken after endometriosis excision. Unexpectedly, raloxifene significantly shortened the time to return of pain (Stratton et al., 2008; Table II). At second laparoscopy, many women in both groups had biopsy-proven endometriosis; those taking raloxifene underwent second surgery significantly sooner, and raloxifene use, but not endometriosis, was associated with return of pain. Because recurrence of endometriosis lesions was not associated with return of pain, estrogen or factors other than the lesions per se, likely caused their pelvic pain.

330

Stratton and Berkley

Table II Current treatments for endometriosis-associated pain. Analgesic efficacy Hormones

Includes both NSAIDS and opioids NSAIDS alleviate dysmenorrhea Use and efficacy of analgesics not assessed in hormonal or surgical endometriosis studies Agents shown to reduce pain

Agents ineffective in pain reduction Other effects of hormonal agents

Surgery

Progestagens Route Oral IUD Depot injection GnRH agonists Danazol Combined hormonal Contraceptives Route Oral Transvaginal Transcutaneous Dosing Cyclic use Continuous use Aromatase inhibitors Only used in combination with oral contraceptives In selected cases, appear to be effective Antiprogestins Effective in small studies but not tested in large populations SERM—raloxifene Shortened time to return of pain after surgical removal of lesions Known and studied effects Thins endometrium, decreases menstrual flow Decidualizes endometrium Prevents ovulation Possible, as yet unstudied effects on pain Alterations of CNS activity Influences of estrogen and progestagens Decreases in blood flow to the uterus or pelvis (GnRH analogues)

Can be effective over short-term High recurrence of pain symptoms may be due to:

Remodeling of CNS (some of which occurred before surgery) Role of reproductive tract in reactivating pain Incomplete removal (that may also increase pain) due to: Poor technical skill because of difficult lesion locations Lack of recognition of variable appearance of lesions Recurrence of lesions

Surgical studies difficult to design and conduct due to:

Poor recognition of the variable appearance and location of lesions High loss to follow-up Need to treat recurrence of pain symptoms Underreporting of analgesic, hormonal and alternative medication Poorly standardized approach to diagnosis Visual inspection—but variable appearance Histologic confirmation—but may be technically difficult to obtain or false negative Poorly standardized approach to correlating lesions and pain No standardized recording of pain location and lesion location Types of lesions may not be equivalent in their role in pain DIE most associated with pain symptoms Location—hyperalgesia in the cul de sac Lesion appearance may not be equivalent in the role in pain Poorly standardized approach to treatment Evolving technology Many surgical tools that may not be equally effective Excision versus ablation Timing of surgery during the menstrual cycle Poorly understood role of adhesions (which may be underreported) formed as a result of surgery have unknown effect on symptom recurrence Mechanical Engage the CNS, possibly innervated Associated with endometriosis lesions

331

Relationship between pain and endometriosis

Novel treatments The higher levels of peritoneal macrophages in endometriosis compared with healthy women (Weinberg et al., 1991) and the finding that endometriosis activates prostaglandins to perpetuate local inflammation (Taylor et al., 1997; Bulun, 2009) suggest that local inflammation is a critical contributor to the relationship between pain and endometriosis. Thus, one new focus of treatments involves agents that can inhibit immunological and inflammatory factors, including angiogenesis inhibitors (Becker and D’Amato, 2007; May and Becker, 2008), tumor necrosis factor-alpha (TNF-alpha; Barrier et al., 2004; Koninckx et al., 2008) and peroxisome proliferators-activated receptors gamma (Pritts et al., 2002; Tee et al., 2006). Of those studied in clinical trials, TNF-alpha antagonists have not been shown to be effective (Koninckx et al., 2008; Lv et al., 2010). Chinese herbal therapy appears also to inhibit immunological and inflammatory factors in vitro (Wieser et al., 2007, 2009) and has shown some efficacy in clinical trials for endometriosis-associated pain (Flower et al., 2009).

Surgery The approach to surgical treatment of endometriosis in women with CPP is based on the oncologic principle of removing all lesions (Howard, 2003; Vercellini et al., 2009b). Yet, pain recurrence and re-operation rates are very high, with re-operation rates for symptoms of 50–60% by 5– 7 years (Cheong et al., 2008; Shakiba et al., 2008). In the 19–29 year age group, over 70% have another surgery. Shakiba et al. (2008) reported that re-operation rates for symptoms are lower after hysterectomy than after operative laparoscopy, a finding also reported by Endometriosis Association members (Sinaii et al., 2007), suggesting the uterus itself contributes to pain in these women. Furthermore, not all women undergoing re-operation have endometriosis at second surgery (Vercellini et al., 2009b), which likely reflects independent central neural contributions to pain or that pain is due to something other than endometriosis. Only three published randomized clinical studies evaluate the effectiveness of surgery (Sutton et al., 1994, 1997; Jones et al., 2001; Abbott et al., 2004; Jarrell et al., 2005; Table II). In these well-designed studies, limited sample size (131 women total), brief follow-up, and loss to follow-up severely hampered evaluating long-term relief of symptoms after surgery. In contrast, large numbers of published observational and retrospective studies illustrate that some surgeons publish good experience and that surgery is operator-dependent. The variable appearance and location of lesions renders surgical diagnosis of endometriosis and treatment of lesions complex (Table II). These issues contribute to the dilemma of determining which lesions contribute to pain. For example, one clinical study (for infertility) accepted only bluish-black lesions as documentation of endometriosis (Marcoux et al., 1997). The variability across studies in lesion criteria and whether all visible, suspicious lesions were identified and treated further compounds the difficulty in understanding which lesions cause pain. An important yet unstudied issue is the surgical technique used to treat lesions (Table II). Superficial lesions may be ablated (destroyed in place) or excised (removed). Whereas ablating lesions is technically easier, ablation may promote adhesions. The charred tissue itself can be interpreted as endometriosis at subsequent surgery, especially if not biopsied. Prospective studies comparing techniques have not been conducted as each surgeon chooses the technique they prefer and their skill by technique may vary.

Treating endometriomas is not straightforward as their association with pain is unclear (Chapron et al., 2002; Vercellini et al., 2009b). Although excision of the pseudocapsule helps to prevent recurrence, excision may lead to diminished ovarian reserve, subsequent infertility and premature ovarian insufficiency (Vercellini et al., 2006b, 2009b). Treating DIE lesions has a greater potential for benefit than treating other lesion types (Fauconnier and Chapron, 2005; Vercellini et al., 2009b). However, DIE surgeries have more complications (3–10%), including blood loss, hemoperitoneum, fistula formation, pelvic abscess and bladder denervation. These complications underscore that DIE treatment requires advanced surgical skill and may require assistance of other specialists including gastrointestinal surgeons, pelvic/reconstructive surgeons, urologists or urogynecologists. Timing of surgery during the menstrual cycle may be important in preventing recurrent disease, adhesions and symptoms (Schweppe and Ring, 2002; Table II). As peritoneal healing takes 3 –5 days, if retrograde menstruation occurs on healing peritoneum, endometriosis and adhesions may immediately reform. This scenario parallels an in vitro model for endometriosis used by Schenken (Witz et al., 2002). Thus, some surgeons favor operating only in the woman’s follicular phase after menses (Koh and Janik, 2002; Schweppe and Ring, 2002), but most studies do not report menstrual phase at surgery. A complicating factor is that adhesions, lysed at surgery, form again (Parker et al., 2005; Table II). Sites of adhesions with or without endometriosis at index surgery are more likely to reform adhesions than sites of endometriosis lesions alone. Thick adhesions are more likely to reform than thin ones. Yet, whether these adhesions contribute to return of pain symptoms is unknown. Studies on the effectiveness of surgery for symptomatic endometriosis illustrate that 20% of patients do not have relief after surgery and those who fail are more likely to have minimal or mild endometriosis (Sutton et al., 1994; Abbott et al., 2004; Jarrell et al., 2005). Furthermore, pain symptoms return sooner in women with minimal or mild endometriosis than those with moderate or severe disease (Sutton et al., 1994). Others report that stage of disease is not associated with differences in time to repeat surgical treatment (Jarrell et al., 2007). Furthermore, in case series, women with rectovaginal disease also experience lesion recurrence (Fedele et al., 2004; Brouwer and Woods, 2007; Kristensen and Kjer, 2007) and 25% undergo repetitive conservative or definitive surgery to treat pain relapse (Reich et al., 1991; Nezhat et al., 1992; Mohr et al., 2005; Mereu et al., 2007). Finally, other surgical strategies have failed in women with endometriosis and pain. Redwine removed all pelvic peritoneum, yet symptoms and some endometriosis returned (Redwine, 1997; Redwine and Wright, 2001). Endometriosis-associated dysmenorrhea treated by either laparoscopic uterine nerve ablation or presacral neurectomy had mixed results (Gambone et al., 2002; Proctor et al., 2005; Daniels et al., 2009). Similarly, locating and excising painful peritoneal areas during laparoscopy by conscious pain mapping had limited success (Howard et al., 2000; Steege, 2001).

Summary and implications of treatments Three types of treatment alleviate pain in women with endometriosis: non-steroidal (NSAID) and other analgesics, hormonal agents and surgical treatment of the lesions. The fact that NSAIDs alleviate pain in some women suggests that endometriosis increases pro-inflammatory agents

332 that, in turn, contribute to pain. Although much is known about how these agents affect lesions (Kyama et al., 2009), little is known about how pro-inflammatory factors contribute to pain symptoms other than the consensus that their release into peritoneal fluid could activate nearby sensory fibers, thereby eliciting pain (Bulun, 2009). Furthermore, other factors are likely involved because NSAIDs are often ineffective (Allen et al., 2009), even when combined with surgical removal of lesions or hormonal therapy (Kennedy et al., 2005; Appleyard et al., 2006; Ozawa et al., 2006; Practice Committee of the American Society for Reproductive and Medicine, 2008; Vercellini et al., 2009b) The fact that hormonal treatments that reduce estradiol levels or influence progesterone alleviate pain in women with endometriosis supports the conclusion that estradiol contributes to pain symptoms and that progestogens may contribute to decreased symptoms (Fedele et al., 2008; Huang, 2008; Aghajanova et al., 2009). Again, however, how hormones exert their effects on pain in endometriosis is poorly understood. For example, whereas ‘progesterone resistance’ may be important in the development of endometriosis, whether endometriosis-associated pain stems from ‘progesterone resistance’ is unknown. Furthermore, other factors are involved, because hormonal treatments do not alleviate pain in all women with endometriosis (Vercellini et al., 2003a; Attar and Bulun, 2006; Jenkins et al., 2008), yet leuprolide relieves pain in women, regardless of whether they have endometriosis (Ling, 1999, Jenkins et al., 2008). The fact that surgical removal or destruction of lesions alleviates pain in some patients indicates that lesions contribute to pain (Vercellini et al., 2009b), but how they do so is poorly understood. First, seemingly complete surgical removal fails to alleviate pain for at least a year in up to 50% of carefully selected patients (Vercellini et al., 2009b). Second, even in patients whose pain was alleviated by surgically treating lesions, pain often returns, sometimes without evidence of new lesions (Abbott et al., 2003; Vercellini et al., 2009b). Third, severity of pain symptoms does not correlate with extent of disease (Kennedy et al., 2005; Vercellini et al., 2009b). Fourth, patients with the least amount of disease, appear more likely to re-experience pain soon after surgery (Sutton et al., 1994). Thus, pain symptoms experienced by those with few lesions may reflect a remodeling of the CNS that is not affected by removing those lesions. Fifth, in the absence of tissue diagnosis, especially with minimal or mild disease, it is unknown whether these women have endometriosis and, thus, whether their potential lesions contribute to their pain. Sixth, as surgical treatment is likely operator-dependent, not only may some surgeons be more skilled in completely removing lesions, but skill in recognizing variable lesion appearance may differ. Seventh, while some lesions are associated with pain more than others, such as DIE versus ovarian endometriomas (Koninckx et al., 1991; Fauconnier and Chapron, 2005), the basis for this difference is not yet understood. Research so far encourages consideration of endometriosis as a chronic inflammatory disease, which unfortunately means that in most cases a single laparoscopic procedure or a 3–6-month medication prescription will not be sufficient. Currently, we cannot predict which women will experience lasting relief of pain symptoms by surgical removal of lesions. Nor can we predict which women will be relieved by medications taken long-term, like oral contraceptive pills. As yet unstudied is whether those with worsening pain with hormonal treatment have progesterone resistance (Ryan and Taylor, 1997; Osteen et al., 2005). Novel treatments like Chinese herbal medications that inhibit angiogenesis and inflammation observed with endometriosis need more study and

Stratton and Berkley

whether their potential efficacy is related to neural effects is discussed below. Similar to other pain conditions, endometriosis encourages a multi-therapeutic approach to its treatment (Table III).

Neural mechanisms of pain in endometriosis Engaging the nervous system In order to understand how endometriosis is associated with pain, it is worthwhile to begin with first principles: pain for any individual is created by activity in that individual’s CNS. Thus, the question becomes, how and under what circumstances does endometriosis engage the CNS to evoke different pain symptoms (Lundeberg and Lund, 2008; Bulun, 2009; Wang et al., 2009)? Few hypotheses address how lesions engage the CNS to produce pain. Lesions may produce pain by compressing or infiltrating nerves near lesions (Woolf, 1996; Ramer and Bisby, 1999; Anaf et al., 2000). The presence of nerve growth factor (NGF) in lesions may be involved, especially in deep adenomyotic nodules where it correlates with hyperalgesia, defined as intense pain reported when pressure is exerted in the posterior fornix (Anaf et al., 2002). NGF can also act on those nerves to produce pain and facilitate nerve growth (Mendell et al., 1999; Cheng and Ji, 2008). Tamburro et al. (2003) report an association between dysmenorrhea severity and transforming growth factor beta1 (TGFb1) in nerve fiber bundles adjacent to endometriotic lesions; more TGFb1 is found in lesions that are either DIE or red compared with black lesions or healthy peritoneum. The concept of surrounding or compressing nearby nerves does not explain pain in situations where nerves are not near lesions. Indeed, pelvic pain is not correlated with nerve fibers in adhesions, peritoneum or within endometriomas (visualized by antibodies to neurofilament protein (Tulandi et al., 1998; Tulandi et al., 2001; Al-Fozan et al., 2004). Importantly, however, these studies call attention to ‘nerves’. Endometriosis lesions must be vascularized to attach and survive (May and Becker, 2008). Importantly, blood vessels are innervated by sensory and sympathetic fibers (Burnstock, 2009) such that factors that act on sprouting blood vessels also act on nerve fibers [vascular endothelial growth factor (VEGF), NGF, semaphorins, netrins, slits and membrane-bound ephrins; Carmeliet and TessierLavigne, 2005; Jones and Li, 2007; Raab and Plate, 2007). Thus, when blood vessels branch to vascularize developing lesions (‘angiogenesis’), nerves innervating those blood vessels may also branch (‘neural sprouting’) thereby enabling nerves to invade lesions. Direct innervation of ectopic endometrial growths by sensory and sympathetic fibers was shown in endometriosis growths from a rat model (Berkley et al., 2004) and lesions from women (Berkley et al., 2005). Finding that lesions can be directly innervated by newly sprouted fibers gave rise to a new conceptualization of mechanisms underlying pain in endometriosis: characteristics of the ectopic growths’ newly formed nerve supply and resultant two-way communication between the growths and CNS contribute to the variable association between the growths and pain (Berkley et al., 2005). Such sprouting, especially if associated with NGF likely sensitizes sensory fibers (Mendell et al., 1999), meaning that their spontaneous activity is greater or they are more easily activated by stimulation.

333

Relationship between pain and endometriosis

Table III Multitherapeutic approach to treatment of endometriosis-associated pain. Drugs

Somatic

Situational

............................................................................................................................................................................................. Primary analgesics NSAIDS acetaminophen opioids Hormonal treatments corticosteroids sex steroids Other agents b-adrenergic antagonists antidepressants anticonvulsants Ca++ channel blockers cox 2 inhibitors GABAB antagonists serotonin antagonists cannabinoids

Adjuvants antihistamines laxatives neuroleptics phenothiazines Routes oral intravenous intramuscular intraperitoneal buccal sublingual intranasal vaginal rectal topical transdermal epidural intrathecal

Simple heat cold exercise massage vibration relaxation sleep Minimally invasive physical therapy botulinum toxin A traction manipulation local anesthesia TENS acupuncture ultrasound

Invasive ablative surgery excisional surgery bilateral salpingooophorectomy hysterectomy lysis of adhesions neurectomy nerve block dorsal column stimulation local ganglion blocks radiation brain stimulation brain focal ablation

Clinician education attitude clinic arrangement Self meditation art poetry music theatre diet herbals virtual reality sports humor gardening aroma therapy religion pets

Interactive hypnosis biofeedback support groups advocacy groups networking self-help groups Structured settings group therapy family counseling job counseling cognitive therapy behavioral therapy psychotherapy multidisciplinary clinic

This table is modified with permission from Berkley (1997).

In clinical studies, using immunohistochemical techniques to mark various neuronal fiber types, Fraser’s group demonstrated sensory, sympathetic and parasympathetic fibers in different types of lesions, reporting that innervation is denser in DIE than other lesion types, and densest in rectal DIE lesions (Tokushige et al., 2006b; Fraser et al., 2008; Wang et al., 2009). Importantly, Mechsner et al. (2009) found that nerve fiber density correlated with severity of pelvic pain or dysmenorrhea.

Evidence from a rodent model Mechanisms by which this new nerve supply could contribute to pain are being studied in a rat model (Berkley et al., 2004). The model involves autotransplanting pieces of uterine horn (ENDO), or fat (shamENDO) on abdominal arteries (Vernon and Wilson, 1985). The uterine, but not fat transplants become vascularized and grow rapidly in the first month, stabilize by 2 months, and remain viable .10 months (Vernon and Wilson, 1985). The ENDO model displays pain symptoms like those occurring in women with endometriosis. ENDO rats develop vaginal hyperalgesia (Cason et al., 2003), which is accompanied by increased abdominal muscle activity (Nagabukuro and Berkley, 2007b). As in women, symptom severity in ENDO rats does not correlate with the volume of ectopic growths (Nagabukuro and Berkley, 2007b). Table IV lists currently known similarities and differences between this rat model and women with endometriosis. Despite the differences, studies using the model provide clues for how the ectopic growths’ nerve supply could contribute to pain in women via peripheral and central neural factors (Fig. 1).

Peripheral factors, general and hormonal In the ENDO model, vaginal hyperalgesia severity varies with the ovarian cycle and is paralleled by changes in ectopic cysts (Zhang et al., 2008). As severity decreases, the cysts’ sympathetic innervation,

NGF and VEGF significantly decrease, along with increases in the cysts’ vascularization. Neural changes do not occur in the rat’s eutopic uterus. In addition, both sympathetic and sensory fibers in cysts co-label with antibodies to the NGF receptor (TrkA), indicating that NGF can act on both types (Sofroniew et al., 2001). The findings imply that cysts are directly conveying hormonally modifiable information to the CNS while simultaneously receiving hormonally modifiable information from the CNS (Fig. 1, Part 1). Similar functional interlinking between sympathetic and sensory innervation is found in other animal and human neuropathic and chronic pain conditions (Janig et al., 1996). Zhang et al. (2008) suggested that endometriosis is a ‘neurovascular condition’ (much like headache), a concept that was also suggested clinically (Giamberardino et al., 2001; Bendtsen, 2003; Calandre et al., 2006; Evans et al., 2007). The rat data suggest that, within ectopic growths, at least four features contribute to severity of endometriosis pain: (i) systemic and local hormonal environment; (ii) local growth factor environment; (iii) vascularity; and (iv) cysts’ sensory and sympathetic innervation. Sympathetic nerve involvement and peripheral estradiol modulation are being studied in women. Possover et al. (2009) found a strong association between sympathetic fibers and blood vessels in endometriosis lesions infiltrating uterosacral ligaments. However, correlation with patients’ symptoms was not assessed. Signorile et al. (2009) reported a significant correlation between the immunohistochemical presence of estrogen receptor alpha, progesterone receptors, nerve fibers and vascularity in rectovaginal DIE lesions. Although immunohistochemical parameters did not correlate with scores of disease, symptoms or contraceptive steroid use, 92% of women had CPP. Stratton et al. (2008) found an association between raloxifene use and accelerated return of pain after surgery. Because raloxifene use likely increases circulating estradiol levels (Baker et al., 1998), these findings support the potential role of peripheral or central estradiol modulation.

334

Stratton and Berkley

Table IV Rodent model of endometriosis: comparison with endometriosis in women. Lesions/symptoms/ innervation of lesions

Rat model of endometriosis

Women with endometriosis

References rat

References human

............................................................................................................................................................................................. Lesions Etiology of lesions

Surgically induced

Endogenous origin (several hypotheses)

Vernon and Wilson (1985)

Giudice and Kao (2004), Bulun (2009)

Location of lesions

Restricted to abdomen

Varied, but predominately pelvic cavity

Vernon and Wilson (1985)

Giudice and Kao (2004), Stegmann et al. (2009)

Appearance/ composition of lesions

Cystic; includes full uterine horn (i.e. endometrium, myometrium and stroma)

Varied appearance (see text): mainly endometrium and stroma

Vernon and Wilson (1985)

Fauconnier and Chapron (2005), Stegmann et al. (2009)

Dysmenorrhea

No (rats do not menstruate)

Yes

Dyspareunia/vaginal hyperalgesia

Yes (vaginal hyperalgesia)

Yes (dyspareunia)

Cason et al. (2003)

Ovarian cyclicity of dyspareunia

Correlates with estradiol levels and uterine contractions

Unknown

Cason et al. (2003), Wray and Noble (2008)

Referred muscle hyperalgesia

Yes

Yes

Nagabukuro and Berkley (2007b)

Jarrell (2004)

Location of referred muscle pain

Abdomen

Pelvic regions/abdomen

Nagabukuro and Berkley (2007b)

Jarrell (2004)

Ovarian cyclicity of referred hyperalgesia

Yes: correlates with estradiol levels and uterine contractions

Unknown

Nagabukuro and Berkley (2007b), Wray and Noble (2008)

Urological symptoms

Hyperreflexia

Increased frequency/urgency

Morrison et al. (2006)

Heitkemper and Jarrett (2005), Vercellini et al. (2009c)

Pain associated with kidney stones

Increased

Likely increased; becomes more cyclic

Giamberardino et al. (2002)

Giamberardino et al. (2001)

Sensory innervation of cysts/lesions

Yes

Yes

Berkley et al. (2004)

Berkley et al. (2005), Tokushige et al. (2006b)

Sympathetic innervation of cysts/ lesions

Yes

Yes

Berkley et al. (2004)

Berkley et al. (2005), Tokushige et al. (2006b)

Hormonal influences on cyst/lesion innervation

Correlates with estradiol levels, dyspareunia symptoms, and uterine contractions

Innervation is reduced by Rx with progestogens or combined oral contraceptives

Wray and Noble (2008), Zhang et al. (2008)

Tokushige et al. (2008)

Symptoms Fauconnier and Chapron (2005) Anaf et al. (2002)

Innervation of lesions

Peripheral factors, peripheral sensitization Sensory fibers whose branches innervate ectopic growths immunostain with antibodies to calcitonin gene-related peptide (CGRP) (Berkley et al., 2004, 2005), indicating that the CGRP-positive fibers include C-fiber nociceptors (Snider and McMahon, 1998). Nociceptors are peripheral sensory detectors that respond to a noxious stimulus, defined as one that is potentially or actually injurious (Merskey and Bogduk, 1994; Sherrington, 1906). Many C-fiber nociceptors are normally ‘silent’ (Cervero and Janig, 1992; Michaelis et al., 1996); when activated by noxious events such as inflammation, not only do they convey information to the CNS (afferent function), but they also can release substance P, CGRP, tachykinins, somatostatin, nitric oxide and other factors into the local environment (efferent function). Once activated, C-fibers can become sensitized, meaning that they no longer remain silent even after inflammation resolves (Gebhart, 1999; Fig. 1, Part 1). Efferent actions

also increase local vascular permeability and inflammation, a process called ‘neurogenic inflammation’ (Holzer, 1998, Szolcsanyi, 2004). Sensory fibers innervating ENDO rats’ ectopic growths are derived from pre-existing nerve fibers that innervate adjacent regions (Zhang et al., 2008). This branching of CGRP-positive sensory fibers strongly suggests that they have become sensitized (Janig et al., 1996), meaning they exhibit ongoing electrical activity (Dmitrieva et al., 2009).

Central factors, general and hormonal Findings from the rat model strongly implicate CNS contributions and their modulation by estradiol, likely triggered by sensitized innervation of the growths (Fig. 1, Part 2). First, effects of ENDO on nociception (Table IV) occur in pelvic/abdominal regions (bladder, vagina, abdominal muscle and mid-ureter). Afferent fibers from these regions enter spinal segments at a different level from neural input from cysts.

335

Relationship between pain and endometriosis

This anatomical separation suggests that intersegmental neural processing occurs (Fig. 1, Part 3). Second, ENDO’s effects on abdominal muscle activity and vaginal hyperalgesia are significantly greater when estradiol is high than when low. These effects may reflect estradiol modulation of neuronal processing within the CNS (Evrard and Balthazart, 2003; Ji et al., 2003b, 2005; Evrard and Balthazart, 2004; Tang et al., 2008) rather than estradiol’s direct effects on cysts or peritoneal environment (Cason et al., 2003; Nagabukuro and Berkley, 2007b). Third, completely removing the cysts abolishes ENDO-induced vaginal hyperalgesia, but returns when rats undergo reproductive senescence (McAllister et al., 2009) at which time their estradiol levels, unlike women and mice, increase significantly (Lu et al., 1979; Berkley et al., 2007). Thus, the CNS can retain a ‘memory’ of central neuronal changes induced by the cysts’ neural input that can be ‘recalled’ by estradiol actions on activity of CNS neurons. Fourth, ENDO-induced vaginal hyperalgesia increases when cysts are incompletely removed (McAllister et al., 2009). Surgery may exacerbate the activity of peripheral afferent fibers remaining in cysts. However, because increased vaginal hyperalgesia occurs in this situation even when estradiol levels are low, CNS neurons may be released from estradiol modulation in cycling rats. Fifth, ENDO, but not shamENDO, increases activation by bladder distention of spinal neurons located in the L6/S1 spinal segments (McGinty et al., 2009), directly supporting central involvement in vaginal hyperalgesia.

Central factors, central sensitization These rat model findings suggest that central sensitization, a process thought to underlie pain hypersensitivity, is an important mechanism

Figure 1 This figure illustrates how endometrial lesions can engage the nervous system to give rise to different types of pain associated with endometriosis and co-morbid conditions. Part 1: This part of the diagram depicts the usual laparoscopic view of pelvic organs (seen by inserting the laparoscope at the umbilicus looking towards the reproductive organs) in which a deeply infiltrating lesion on the left uterosacral ligament is expanded in the inset. Both peptidergic sensory (blue) and sympathetic nerve fibers (green) sprout axon branches (red dashed lines) from nerve fibers that innervate nearby blood vessels to innervate this lesion. Sensory fibers that sprouted new axons become sensitized (red asterisk). The extent of sensitization is dynamically-modulated by estradiol and sympathetic-sensory coupling. Part 2: Two-way connection between innervated lesions and spinal cord is concentrated within sacral segments of the pelvic region. Sensitized peripheral nerve fibers, in turn, sensitize spinal sacral segment neurons. This ‘central sensitization’, shown by the red asterisk in the sacral segment, can become independent of and is modulated differently from peripheral sensitization, described in the text. Part 3: Although input from peripheral afferent fibers to the spinal cord via their dorsal roots is concentrated in the segment associated with the body part the fibers innervate (sacral segments), branches of the fibers extend to other segments (blue dashed lines). Normally, these dorsal root branches have minimal impact on neurons in other segments unless the fibers become sensitized. If, however, the fibers become sensitized, they can in turn sensitize neurons in the other segments. Such remote actions are depicted by

red dashed branches into the lumbar, thoracic and cervical spinal cord dorsal horn and the red asterisks at those levels. Part 4: Normally, multiple intersegmental spinal connections exist to coordinate healthy bodily functions via excitatory and inhibitory synaptic connections, shown by double-arrowed black lines. This intersegmental communication can influence how central sensitization modifies how neurons in remote segments process nociceptive and nonnociceptive sensory information (‘remote central sensitization’), shown as red asterisks. Together, actions in Parts 3 and 4 can lead to increased nociception not only at sacral entry segments but also in any other segment. Part 5: Multiple connections exist that ascend from every level of the spinal cord to the brain (shown by blue lines) and descend from the brain to the spinal cord (shown by green lines). Thus, in health, input from the spinal cord engages neurons throughout the brain that themselves are interconnected via complex ascending and descending inhibitory/excitatory synapses. Input from sensitized spinal neurons can affect activity throughout the neuroaxis, altering normal processing of nociceptive and non-nociceptive information. Some regions that can be influenced are depicted by red asterisks. Although asterisks are shown on the medial surface of the cortex, some influenced areas extend to parts of the lateral prefrontal, frontal, parietal lobes and within the temporal lobe (dotted black ellipses). These influences can become independent of peripheral sensitization associated with lesions’ innvervation (Part 1). Such actions provide mechanisms for different types of endometriosis-associated and co-morbid pain, not only in the pelvis, but also elsewhere.

336 contributing, along with peripheral sensitization, to the association between endometriosis and pain (Woolf, 1983; McMahon, 1991; Coderre et al., 1993; Giamberardino et al., 1997; Ren and Dubner, 1999; Melzack et al., 2001; Ji et al., 2003b; DeLeo, 2006; Woolf and Ma, 2007; Ren and Dubner, 2008; Fig. 1, Parts 2– 5, asterisks). Central sensitization is defined as ‘an increase in the excitability of the CNS so that normal inputs now evoke exaggerated responses’ (Woolf, 1983). Clinical evidence suggests this concept applies to painful endometriosis in women (Bajaj et al., 2003). Central sensitization is initiated by peripheral sensitization (Fig. 1) and maintained by continued input to the CNS from sensitized sensory afferent fibers (Woolf and Salter, 2000). Changes in activity of peripherally sensitized fibers, due to estradiol and sympathetic modulation in the rat model, can ‘modulate’ activity of centrally sensitized neurons to affect pain severity (Woolf and Salter, 2000). Elimination of sensitized input, such as removal of ectopic growths, would relieve pain. Sometimes, however, central neural processing can be ‘modified’ so that initially peripherally induced central sensitization becomes independent of peripheral sensitization (Woolf and Salter, 2000) via neural mechanisms similar to those underlying memory (Melzack et al., 2001; Ji et al., 2003a; Ren and Dubner, 2007). The pain then remains long after the initiating pathophysiology resolves. As a result, therapies directed at the periphery, including removal of ectopic growths or medical therapy to alter them, fail to relieve pain, and pain becomes difficult to treat.

Viscero-visceral CNS connections or cross-organ effects Finding other pain syndromes such as painful bladder or irritable bowel syndrome in women with endometriosis-associated pain suggests that mechanisms underlying cross-talk between viscera contribute to pain, as they do in the rat model (Giamberardino et al., 2002; Morrison et al., 2006). Li et al. (2008), provide evidence in rodents that uterine inflammation can directly affect the colon via increased phosphorylated extracellular signal-regulated kinase (pERK) and substance P in peripheral sensory neurons (dorsal root ganglion, DRG, neurons) that branch to supply both organs. However, most DRG neurons supply one organ, rarely branching to supply more than one (Winnard et al., 2006; Li et al., 2008). Therefore, most cross-organ effects likely arise from convergence of input from different organs on spinal cord neurons.

Estradiol’s influence on CNS function Estradiol can influence sensitivity of peripheral sensory neurons as well as sympathetic nerve actions on those neurons (Komisaruk et al., 1972; Kow and Pfaff, 1973; Adler et al., 1977; Kaur et al., 2007). Further, evidence suggests estradiol modulates central neuronal activity in pain states (Craft et al., 2004; Greenspan et al., 2007). For example, alterations in circulating estradiol produce complex alterations in how neurons in the thalamus process information concerning the reproductive organs, colon and skin (Reed et al., 2009).

Endometriosis: peripheral sensitization, central sensitization, central neural circuitry and estradiol Information processing by the highly interconnected CNS circuitry can be significantly influenced by peripheral sensitization in endometriosis

Stratton and Berkley

(Fig. 1). Thus, sensitized inputs from ectopic growths can influence neuronal activity throughout the CNS by unmasking latent, or by altering existing excitatory or inhibitory processes. Some central effects are maintained by continued input from the ectopic growth’s sensory fibers, which themselves are modulated by estradiol and activity in sympathetic fibers. Production of local peritoneal factors by implants themselves, or during menstruation or ovulation may also contribute to maintaining continued input to the CNS. Further, other central actions can become independent of any peripheral input from ectopic growths due to long-term ‘modification’ of CNS functioning. All central effects can be modulated by estradiol. Most central sensitization occurs at the spinal entry region of sensitized peripheral afferent fibers (Fig. 1, Part 2). Thus, in women, pain occurs mostly in the pelvis because most lesions are located there (Vercellini et al., 2007; Bricou et al., 2008). Pain would involve not only direct association with innervated-lesion-endowed pelvic reproductive organs, but also pains referred to abdomino-pelvic muscles, bladder and colon. Importantly, ‘remote’ central sensitization can also occur via long-ranging peripheral sensory fibers from disparate parts of the body and enormous CNS interconnectivity (Fig. 1, Parts 3–5). For women, remote central sensitization could account for co-morbidity of pelvic pain with other pain syndromes such as temporomandibular joint disorder or fibromyalgia (Sinaii et al., 2002; DeSantana and Sluka, 2008). Further, estradioldependence of endometriosis’s pain symptoms can be partly explained by estradiol’s effects on central neuronal functioning.

Potential therapies directed at neural involvement in pain Pain researchers are beginning to study treatments based on the presumed mechanism of the patient’s pain rather than disease associated with pain (Woolf, 2004), for example, neuropathic pain (Dworkin et al., 2010). Endometriosis has not yet been widely recognized as a disease associated with neural dysfunction such as central sensitization, and thus therapies directed at the nervous system have not yet been studied in clinical trials of endometriosis-associated pain. However, endometriosis researchers are beginning to focus on novel compounds that ultimately may have neural affects via growth factors, inflammation, angiogenesis inhibitors and the endocannabinoid system (Becker and D’Amato, 2007; Nagabukuro and Berkley, 2007a; Oktem et al., 2007; Zhang et al., 2008; Dmitrieva et al., in press). Furthermore, because hormonal and surgical therapies are too often unsuccessful in the long-term, women and clinicians have in fact resorted to multi-therapeutic strategies commonly used in management of chronic pain (Schatman and Campbell, 2007;Berkley and Stratton, 2009; Table III).

Neuroimmune and neuroendocrine factors Cytokines, illness response and sensitivity to pain Altered cytokine production resulting in elevated pro-inflammatory cytokines is a key aspect of chronic pain states. Chronic pain in animal models is associated with increased pro-inflammatory

337

Relationship between pain and endometriosis

cytokines in systemic circulation (Walters, 1994; Watkins et al., 1995a, b; Wieseler-Frank et al., 2005). Administration of inflammatory cytokines TNFa, interleukin-1 (IL-1) and IL-6 in animal models produces both the illness response and increased sensitivity to noxious stimuli (Berczi et al., 1998; Coelho et al., 2000; Wieseler-Frank et al., 2005). Lipopolysaccharide administered peripherally in rodents results in enhanced pro-inflammatory cytokine expression and marked hyperalgesia that is abolished by administration of an IL-1 receptor antagonist (Maier et al., 1993; Taylor et al., 1998; Maier and Watkins, 2003) or TNFa antagonist (Coelho et al., 2000; SafiehGarabedian et al., 2000). These same inflammatory cytokines are elevated in peritoneal fluid (Koninckx et al., 1998; Minici et al., 2007) in women with painful endometriosis and such factors are an important facet of central sensitization (Wieseler-Frank et al., 2005). However, these treatments have not been effective for endometriosis-associated pain (Koninckx et al., 2008).

Hypothalamic pituitary adrenal axis and pain Pain is a stressful experience, and animal models show that the hypothalamic–pituitary–adrenal (HPA) axis is activated during both tonic and phasic pain (Taylor et al., 1998). Monoaminergic neurons in the brain stem usually act as brakes to nociceptive transmission. However, with HPA activation, an increase in glucocorticoid secretion induces monoamine depletion and loss of monoaminergic tone (Blackburn-Munro and Blackburn-Munro, 2003), resulting in increased pain. Chronic stress is associated with enhanced pain (Romero and Sapolsky, 1996). The continuous and prolonged activation of the HPA axis causes the negative feedback loop to become dysregulated, leading to either enhanced hormone production and release or resistance to circulating glucocorticoids (Blackburn-Munro and BlackburnMunro, 2003). Additionally, in chronic stress, loss of glucocorticoid receptor expression can cause a loss of glucocorticoid inhibition of pro-inflammatory cytokines that results in an increase in cytokine levels (Sapolsky et al., 2000). The resulting chain of events can contribute to peripheral sensitization and, eventually, central sensitization. Clinical studies on chronic pain states such as fibromyalgia, rheumatoid arthritis and several autoimmune inflammatory diseases implicate involvement of dysfunctional HPA responsivity (Buyalos et al., 1992; Lentjes et al., 1997; Griep et al., 1998; Bellometti and Galzigna, 1999; Torpy et al., 2000; Crofford, 2002). The same situation likely applies to endometriosis and chronic pain (Stegmann et al., 2008a).

Contributions of the reproductive organs and functions Given that peripheral and central sensitization contribute to pain symptoms, the question then arises as to how reproductive system functioning also contributes. Peripheral factors associated with painful endometriosis are found in women without endometriosis, such as increased eutopic uterine innervation (Quinn and Kirk, 2002; Tokushige et al., 2007; Zhang et al., 2009) and high concentrations of prostaglandins and other pro-inflammatory agents in peritoneal fluid (Koninckx et al., 1998). Dynamic events that repeat monthly during a woman’s menstrual cycle (ovulation, endometrial maturation and shedding) and change over her reproductive life are intertwined.

Menstrual cycle and other reproductive events, like pregnancy, likely influence sensitization and pain in women with endometriosis.

Normal endometrium Throughout the menstrual cycle, the endometrium produces cytokines and growth factors in response to variations in ovarian steroids (Critchley et al., 2006; Jabbour et al., 2006; Collins and Crosignani, 2007; Table V). With withdrawal of progesterone during the premenstrual phase, stroma, endothelium and immune cells undergo changes, inducing local mediators such as chemokines, cytokines, cell regulators and enzymes responsible for prostaglandin synthesis and degradation. These mediators and enzymes, in turn, facilitate influx of leukocytes into tissues (Critchley et al., 2001). VEGF and its receptor VEGFR-2 kinase insert domain receptor (KDR) are markedly up-regulated in superficial endometrial stromal cells in human and non-human primate models (Nayak et al., 2000; Brenner et al., 2002) In all women, menstrual endometrium is rich in leukocytes, chemokines, cytokines, VEGF, KDR, matrix metalloproteinases (MMPs) and prostaglandins (Salamonsen et al., 2002), some of which, if altered, likely contribute to nerve sprouting and perpetuating sensitization. Hormonal treatments may diminish these factors (see review by Vercellini et al., 2003a)

Endometrium in endometriosis and the potential role of progestogens In endometriosis, eutopic endometrium exhibits several subtle but possibly important molecular changes, including cascades favoring increased synthesis of cytokines, prostaglandins, metalloproteinases and estrogen (Giudice and Kao, 2004; Bulun, 2009; Table V). These molecular abnormalities are amplified when shed endometrium attaches to mesothelial cells. These changes serve not only to enhance implant survival, but also may create a local increased production of factors that promote nerve sprouting and peripheral sensitization. A reduction in progesterone action in endometrium, ‘progesterone resistance’, of women with endometriosis (Osteen et al., 2005; Table V) may play a key role in development of endometriosis and possibly with associated pain; use of progestagens may reverse these effects.

Nerves in endometrium An increase of nerve fibers in the endometrium and myometrium was observed in women with endometriosis undergoing endometrial biopsy or hysterectomy compared with other women and women with endometriosis using hormonal treatments (Tokushige et al., 2006a; Al-Jefout et al., 2007; Tokushige et al., 2008; Schulke et al., 2009). This observation was studied further by two groups, who both found that the presence of nerve fibers in endometrium serves as a marker for endometriosis with high specificity and sensitivity (Al-Jefout et al., 2009, Bokor et al., 2009; Table V). The question then arises as to how this potential diagnostic tool relates to endometriosis-associated pain. In Al-Jefout’s study (2009), many factors were examined for their relation to nerve fiber density without performing multivariate comparisons controlling for how these factors might interrelate. It is impossible to determine how many women had pain or how the diagnosis of endometriosis was made (biopsy or visualization), both of which would inform how nerves would serve as a diagnostic tool. Comparison of these factors considering

338

Stratton and Berkley

Table V Role of the reproductive tract. Endometrium and menstruation

Dynamic complex organ that is shed monthly Heavier in women with endometriosis Outflow tract obstruction may play a role in pain and endometriosis May differ in women with endometriosis Progesterone resistance or reduction in progesterone action Growth factor differences Nerves or NGF

Uterus

Leiomyomas, adenomyosis associated with similar pain symptoms Contractions may differ in women with endometriosis

Ovaries and peritoneal fluid

Dynamic complex events with ovulation May differ in women with endometriosis Higher levels of hormonal and inflammatory factors

Pregnancy and delivery

Pseudopregnancy resolves lesions Cervical diameter may contribute to lesions and symptoms

endometriosis (as present or absent) and pain (as present or absent) was not performed, which would also have been informative. In Bokor’s study (2009), a serious limitation is that few women had pain (only five of 40 women: three with endometriosis, two controls). Together, the two studies may indicate that nerve fibers in eutopic endometrium are diagnostic of endometriosis regardless of whether the patient suffers pain. Finding nerves in the functional layer of the endometrium that is shed monthly is a provocative idea that needs replication by others. Currently, however, how endometrial nerves relate to pain specifically associated with endometriosis is unknown because nerve fibers have been found in the uterus of women with pain who do not have endometriosis (Zhang et al., 2009). How to use the information clinically is therefore uncertain. One testable possibility is that nerve growth may be hormonally modulated in eutopic endometrium and contribute to dysmenorrhea. A putative reduction in these fibers by use of progestin-dominant hormonal therapy would then present a rationale for their effectiveness in dysmenorrhea.

Menstruation Retrograde menstruation is the mostly widely believed theory for how endometriosis develops. As most women have retrograde menstruation, genetic, endometrial (via changes in gene expression, hormone-induced receptor changes or other factors), inflammatory and autoimmune factors have been investigated to explain why some women have endometriosis and some do not, but no definitive risk factor has been found (Giudice and Kao, 2004; Bulun, 2009). Women with endometriosis report having heavier menses than those without endometriosis (Treloar et al., 1998; Cramer and Missmer, 2002; Table V). Finding prostaglandins in menstrual effluent with higher levels in women with heavy menses and dysmenorrhea provides a rationale for using NSAIDs to treat dysmenorrhea (Rees et al., 1984a, b; Baird et al., 1996). These prostaglandins, if untreated, could contribute to further inflammation, providing conditions important for perpetuating sensitization. Women with genital tract anomalies obstructing the outflow of menses (Olive and Henderson, 1987; Ugur et al., 1995; Nawroth et al., 2006) frequently have endometriosis and pelvic pain (Table V). When the obstruction is removed, often lesions and pain resolve (Sanfilippo et al., 1986). Similarly, intramural and submucosal uterine fibroids, endometrial polyps, menstrual

collection devices and tubal ligation can cause mechanical obstruction to menstrual flow, and thus may contribute to the pain experienced. No studies address the relationship between cervical or tubal obstruction and pelvic pain, but case reports document relief of symptoms after removal of various obstructions, suggesting an association (Morrissey et al., 2002; Spechler et al., 2003).

Uterus Uterine leiomyomas and adenomyosis are common among women of reproductive age and are associated with pain and heavy bleeding (Spies et al., 2002). Because these conditions may co-exist in women with endometriosis, attributing pain to leiomyomas, adenomyosis or endometriosis is challenging, especially because consensus non-surgical diagnostic criteria for adenomyosis using ultrasound and Magnetic Resonance Imaging (MRI) have not been developed (Vercellini et al., 2006c; Table V). Following surgical excision of endometriosis, Parker et al. (2006) report that CPP is significantly more likely to persist with junctional zone thickness .11 mm on preoperative MRI, suggesting that myometrial junctional zone abnormalities or adenomyosis contribute to CPP in women with endometriosis. Quinn et al. hypothesize that abnormalities in innervation of eutopic uterus contribute to CPP such that small-diameter nerve fibers are present in myometrium of women with pain (but no endometriosis) and around adenomyotic nodules in those with adenomyosis, but not those without pain (Quinn and Kirk, 2002; Quinn and Armstrong, 2004). Others report increased nerve growth in myometrium in those with pain with or without endometriosis compared with healthy women (Atwal et al., 2005; Zhang et al., 2009). The non-pregnant uterus contracts throughout the menstrual cycle (Martinez-Gaudio et al., 1973; Chalubinski et al., 1993; Bulletti et al., 2004). In healthy women, contractions propagate from fundus to cervix during menses, which presumably aids in emptying the uterus of menstrual blood (Martinez-Gaudio et al., 1973). Myometrial contractions do not occur in women on oral contraceptives compared with cycling women (Maslow and Lyons, 2004; Kido et al., 2007) suggesting a hormonal treatment effect on contractions. Since muscle contractions can be increased by prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a), and blunted by use of NSAIDs

339

Relationship between pain and endometriosis

(Maslow and Lyons, 2004), prostaglandins play a role in myometrial contractility, independent of their role in neural sensitization. Contraction patterns may differ in women with endometriosis, leading to hyperkinetic or dyskinetic contractions that impede emptying of menstrual blood or contribute to dysmenorrhea. Mean contraction pressure and frequency is higher and more frequent, and results in more retrograde endometrial debris in women with endometriosis than controls (Salamanca and Beltran, 1995; Bulletti et al., 1996; Leyendecker et al., 1996). This increase in retrograde menstrual debris may deposit more factors that could either induce nerve sprouting or contribute to neurogenic inflammation, and thus lead to continued sensitization.

Ovaries and peritoneal fluid Women with endometriosis usually have regular menstrual cycles of 25 –37 days. In contrast, women who do not have regular menstrual cycles, like those with polycystic ovarian syndrome, usually do not report CPP or have endometriosis (Babaknia et al., 1976). Ovulation is a complex event regulated by the hypothalamicpituitary ovarian axis and also involves local chemokines and other factors related to inflammation (Buscher et al., 1999; Townson and Liptak, 2003; Table V). Within dominant follicles, the steroid hormone level is 100-fold higher than in plasma (Baird and Fraser, 1974). At ovulation, cytokine- and hormone-rich fluid is released into the peritoneal cavity, with levels of hormones and other factors significantly higher than in plasma (Scheenjes et al., 1990, 1991). The amount of fluid and hormones released is greatest midcycle with progesterone levels 60-fold higher and estrogen levels about 10-fold higher than in serum in the luteal phase (Donnez et al., 1982). Fluid volume and hormones released are lower in women taking contraceptive hormones, even with progestin-only contraceptives that do not suppress ovulation (Kim-Bjorklund et al., 1991). This hormone- and cytokine-rich fluid released into the peritoneal cavity with ovulation may contribute to ovulation-related pain in women with endometriosis through neural actions. Women with endometriosis have a higher rate of luteinized unruptured follicles (LUF) than women without endometriosis (Dmowski et al., 1980; Koninckx et al., 1998). Although theorized to contribute to infertility in endometriosis, LUF could also contribute to pain because there is no rise in peritoneal levels of progesterone. Pelvic peritoneal fluid is an ovarian exudate arising from both vascular leakage and release of fluid at ovulation (Koninckx et al., 1998). This fluid contains many macrophages and their secretion products including cytokines, interleukins and others. Endometriosis is associated with a sterile peritoneal inflammation that results in activation of macrophages that release secretory products, such as cytokines, growth and angiogenic factors (Weinberg et al., 1991; Ryan and Taylor 1997). The role of peritoneal fluid in endometriosis is described by Koninckx et al. (1998), but it is reasonable to consider that these factors in fluid potentially stimulate sprouting of nerve fibers, promote their sensitization and further increase release and activation of pro-inflammatory mediators. Some studies suggest that progestins can normalize peritoneal fluid characteristics, which may decrease factors that enhance sensitization and pain. In vivo, dienogest decreases peritoneal fluid macrophage IL-1b production and angiogenesis, normalizes peritoneal fluid cell

number and increases peritoneal fluid cells natural killer activity (Katsuki et al., 1998; Nakamura et al., 1999).

Pregnancy and vaginal delivery After pregnancy, pain often abates (Bulletti et al., 2004). Previously, some theorized that elevated hormones during pregnancy somehow contribute to resolving lesions, which led to use of high dose oral contraceptives to simulate a pseudopregnancy (Olive and Pritts, 2001; Table V). However, Bulletti et al. (2009) recently reported that vaginal delivery itself, rather than high hormone levels in pregnancy, may underlie symptom resolution. This observation comes from a cohort of 350 women with known stage II –IV endometriosis, dysmenorrhea and infertility. Vaginal delivery was associated with a larger internal cervical os diameter than delivery by Cesarean section or women who remained infertile. This wider cervical canal was associated with lower rates of dysmenorrhea and endometriosis recurrence than in the others, an observation that needs confirmation (Table V). Further support for the effects of vaginal delivery is that multiparity is associated with a lower risk of endometriosis (Missmer et al., 2004).

Problems with pain assessments in practice and in clinical studies Endometriosis classification system The ASRM developed a classification system that enables surgeons to describe where lesions are located on reproductive organs, extent and depth of lesions and associated adhesions involving the ovary, fallopian tube or cul de sac (Revised American Society for Reproductive Medicine classification of endometriosis, 1997). This classification system documents surgical findings, but is not useful for predicting outcomes related to infertility or pain (Schenken, 1998; Adamson and Pasta, 2009; Vercellini et al., 2006a) for three reasons. First, pain information is not noted on the form and thus comparison between pain location and lesion location is inconsistently recorded. Second, most clinical studies of pain and endometriosis summarize the ASRM classification as a measure of disease extent, but do not provide details about lesion location. Third, change in endometriosis score has been used to assess treatment effect with the assumption, but no evidence, that lesion score correlates with pain score (Shaw, 1992; Wheeler et al., 1992; Wright et al., 1995; Vercellini et al., 2009b).

Pain assessment Pain is a subjective and complex experience, whose understanding requires good descriptions of its individual characteristics for each patient (Dworkin et al., 2005). Despite this complexity, most endometriosis studies classify dysmenorrhea, dyspareunia and CPP as either absent, mild, moderate or severe, and describe the degree of debility experienced (Biberoglu and Behrman, 1981). This incomplete assessment strategy hampers assessment of pain outcomes (Vincent et al., 2008) and fails to consider diagnostic subtypes of CPP (Leserman et al., 2006), such as those noted with different locations of DIE (Fauconnier et al., 2002). There are efforts underway to standardize the outcome end-point in these studies with the use of visual analogue scales, but other types of scales may be needed (Dionne et al., 2005; Vincent et al., 2008).

340

Comorbidity Before pain can be attributed to endometriosis, differential diagnosis of other causes of pelvic pain should be considered. It is important that pelvic infection and diseases that are primarily myofascial, genitourinary, gastrointestinal and neurologic be investigated and excluded. Such exclusion is necessary to avoid assuming that endometriosis lesions found at surgery are the cause of the woman’s pelvic pain. An additional confounder is that women with endometriosis have a higher rate of other pain syndromes associated with peripheral and central sensitization such as irritable bowel syndrome, painful bladder syndrome, fibromyalgia and migraine headache (Gao et al., 2006; Mirkin et al., 2007; Theoharides, 2007; Tietjen et al., 2007; Vercellini et al., 2009c). In addition, women experiencing chronic pain who have endometriosis may be prone to depression, anxiety and chronic fatigue as seen with chronic fatigue syndrome (Waller and Shaw, 1995; Sinaii et al., 2002). Although the association of endometriosis with these other conditions has not been systematically studied, recognition that there are co-morbid pain conditions, and that, at different times in a woman’s life, one type of pain may dominate over another, and that discomfort associated with pain attributed to endometriosis, such as dysmenorrhea, may be worsened with concomitant bladder symptoms suggests a neurologic overlap. Furthermore, in most women with endometriosis and CPP, there appears to be some concomitant myofascial dysfunction, with abdominal muscle trigger points most indicative of internal pathology (Jarrell, 2004). Muscle spasm findings are similar to those found in the ENDO rat model (Nagabukuro and Berkley, 2007b) and may signify an important facet of pain associated with endometriosis.

Summary, conclusions and future directions Women with endometriosis suffer from a wide spectrum of different types of pain, ranging from ‘simple’ severe dysmenorrhea to chronic pelvic and other co-morbid pain conditions. Current analgesic, antiinflammatory, surgical and hormonal treatments remain unsatisfactory likely because treatments focus on treating or eliminating the growths. Many factors can contribute interactively to individual variability in endometriosis-associated pain. Research so far encourages consideration of endometriosis as a chronic inflammatory disease, which, in turn, encourages a multi-therapeutic approach to its treatment (Table III). Furthermore, because pain of any type resides in nervous system activity, research also suggests that a major contributing factor for endometriosis-pain is not the ectopic growths themselves, but rather how sensory and autonomic nerve activity from nerves that have sprouted from nearby tissues to innervate the growths affect activity of neurons in the spinal cord and brain. Many interacting elements influence pain experienced in women with endometriosis. Some influences include menstruation, uterine and ovarian functions, estrogens, progestins, vaginal delivery, parity, peritoneal fluid, lesion type and lesion location, all of which can affect whether, when and how innervation of growths becomes sensitized, which, in turn, can affect CNS neurons and their peripherally dependent or peripherally independent sensitization (Fig. 1). A major challenge for future

Stratton and Berkley

research is to understand how this independence develops in some women, but not others. The most important message from this literature review, however, is that major advances in improving understanding and alleviating pain in endometriosis will likely occur if the focus changes from lesions to pain: how endometriosis fits within the knowledge of mechanisms that underlie chronic pain conditions in general. Improvements will need to be made in how endometriosis is classified in the context of pain symptoms and how pain is assessed in clinical studies and the clinic. In so doing, novel directions and strategies for treatment may become more apparent as well as how to use these treatments more effectively within a multi-therapeutic strategic approach targeted at the individual’s symptom complex (Berkley and Stratton, 2009; Table III). Overall, therefore, one research area important for improving understanding of the association between pain and endometriosis concerns the dynamics and activational physiology of peripheral nerves that supply lesions. As described here many factors likely contribute. Fundamental for advancing knowledge is recognition that engagement of the CNS by these peripheral neural processes within or near lesions and the resultant potential independence of the CNS from those peripheral processes is pre-eminent, and that research to improve understanding how endometriosis influences the spinal cord and brain of women to evoke pain is badly needed. Thus, CPP associated with endometriosis, is best considered in the context of chronic pain in general. Indeed, one growing area in the field of chronic pain is to understand commonalities across the many different forms of chronic pain (Mayer and Bushnell, 2009).

Acknowledgements Alan Decherney, M.D. for his support in our writing this manuscript, Alan Hoofring of NIH Medical Arts for illustrating the figure in the manuscript and Daniel Martin, MD, Ninet Sinaii, Ph.D., MPH and Edson G. Case, JD, MA, for helpful comments during preparation of the review.

Funding Supported by the Intramural Program, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institutes of Health (P.S.) and NIH grant RO1 NS11892 (K.J.B.)

References Abbott JA, Hawe J, Clayton RD, Garry R. The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2 –5 year follow-up. Hum Reprod 2003;18:1922– 1927. Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril 2004; 82:878– 884. Abou-Setta AM, Al-Inany HG, Farquhar CM. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database Syst Rev 2006;(Issue 4): CD005072. Adamson GD, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril 2009; Epub ahead of print November 18. Adler NT, Davis PG, Komisaruk BR. Variation in the size and sensitivity of a genital sensory field in relation to the estrous cycle in rats. Horm Behav 1977;9:334– 344.

Relationship between pain and endometriosis

Aghajanova L, Hamilton A, Kwintkiewicz J, Vo KC, Giudice LC. Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis. Biol Reprod 2009; 80:105– 114. Al-Fozan H, Bakare S, Chen MF, Tulandi T. Nerve fibers in ovarian dermoid cysts and endometriomas. Fertil Steril 2004;82:230–231. Al-Jefout M, Andreadis N, Tokushige N, Markham R, Fraser I. A pilot study to evaluate the relative efficacy of endometrial biopsy and full curettage in making a diagnosis of endometriosis by the detection of endometrial nerve fibers. Am J Obstet Gynecol 2007;197:578 e571 –574. Al-Jefout M, Dezarnaulds G, Cooper M, Tokushige N, Luscombe GM, Markham R, Fraser IS. Diagnosis of endometriosis by detection of nerve fibres in an endometrial biopsy: a double blind study. Hum Reprod 2009;24:3019 –3024. Albee RB Jr, Sinervo K, Fisher DT. Laparoscopic excision of lesions suggestive of endometriosis or otherwise atypical in appearance: relationship between visual findings and final histologic diagnosis. J Minim Invasive Gynecol 2008;15:32– 37. Allen C, Hopewell S, Prentice A, Gregory D. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev 2009;(Issue 2):CD004753. American Society for Reproductive and Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67:817– 821. Amsterdam LL, Gentry W, Jobanputra S, Wolf M, Rubin SD, Bulun SE. Anastrazole and oral contraceptives: a novel treatment for endometriosis. Fertil Steril 2005; 84:300– 304. Anaf V, Simon P, El Nakadi I, Fayt I, Buxant F, Simonart T, Peny MO, Noel JC. Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod 2000;15:1744 –1750. Anaf V, Simon P, El Nakadi I, Fayt I, Simonart T, Buxant F, Noel JC. Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis. Hum Reprod 2002;17:1895 –1900. Appleyard TL, Mann CH, Khan KS. Guidelines for the management of pelvic pain associated with endometriosis: a systematic appraisal of their quality. BJOG 2006;113:749– 757. Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis. Fertil Steril 2006;85:1307 –1318. Atwal G, du Plessis D, Armstrong G, Slade R, Quinn M. Uterine innervation after hysterectomy for chronic pelvic pain with, and without, endometriosis. Am J Obstet Gynecol 2005;193:1650 –1655. Babaknia A, Calfopoulos P, Jones HW Jr. The Stein-Leventhal syndrome and coincidental ovarian tumors? Obstet Gynecol 1976;47:223–224. Baird DT, Fraser IS. Blood production and ovarian secretion rates of estradiol-17 beta and estrone in women throughout the menstrual cycle. J Clin Endocrinol Metab 1974;38:1009 –1017. Baird DT, Cameron ST, Critchley HO, Drudy TA, Howe A, Jones RL, Lea RG, Kelly RW. Prostaglandins and menstruation. Eur J Obstet Gynecol Reprod Biol 1996;70:15 –17. Bajaj P, Madsen H, Arendt-Nielsen L. Endometriosis is associated with central sensitization: a psychophysical controlled study. J Pain 2003;4:372–380. Baker VL, Draper M, Paul S, Allerheiligen S, Glant M, Shifren J, Jaffe RB. Reproductive endocrine and endometrial effects of raloxifene hydrochloride, a selective estrogen receptor modulator, in women with regular menstrual cycles. J Clin Endocrinol Metab 1998;83:6 – 13. Barrier BF, Bates GW, Leland MM, Leach DA, Robinson RD, Propst AM. Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons. Fertil Steril 2004;81(Suppl 1): 775 –779. Becker CM, D’Amato RJ. Angiogenesis and antiangiogenic therapy in endometriosis. Microvasc Res 2007;74:121– 130. Bellometti S, Galzigna L. Function of the hypothalamic adrenal axis in patients with fibromyalgia syndrome undergoing mud-pack treatment. Int J Clin Pharmacol Res 1999;19:27 –33. Bendtsen L. Central and peripheral sensitization in tension-type headache. Curr Pain Headache Rep 2003;7:460– 465. Berczi I, Chow DA, Sabbadini ER. Neuroimmunoregulation and natural immunity. Domest Anim Endocrinol 1998;15:273– 281. Berkley KJ. On the dorsal columns: translating basic research hypotheses to the clinic. Pain 1997;70:103 –107.

341 Berkley KJ, Stratton P. Mechanisms: lessons from translational studies of endometriosis. In: Giamberardino MA (ed). Visceral Pain: Clinical, Pathophysiological and Therapeutic Aspects. Oxford: Oxford University Press, 2009, 39– 50. Berkley KJ, Dmitrieva N, Curtis KS, Papka RE. Innervation of ectopic endometrium in a rat model of endometriosis. Proc Natl Acad Sci U S A 2004;101:11094–11098. Berkley KJ, Rapkin AJ, Papka RE. The pains of endometriosis. Science 2005; 308:1587 – 1589. Berkley KJ, McAllister SL, Accius BE, Winnard KP. Endometriosis-induced vaginal hyperalgesia in the rat: effect of estropause, ovariectomy, and estradiol replacement. Pain 2007;132(Suppl. 1):S150– 159. Biberoglu KO, Behrman SJ. Dosage aspects of danazol therapy in endometriosis: short-term and long-term effectiveness. Am J Obstet Gynecol 1981;139:645– 654. Blackburn-Munro G, Blackburn-Munro R. Pain in the brain: are hormones to blame? Trends Endocrinol Metab 2003;14:20– 27. Bokor A, Kyama CM, Vercruysse L, Fassbender A, Gevaert O, Vodolazkaia A, De Moor B, Fulop V, D’Hooghe T. Density of small diameter sensory nerve fibres in endometrium: a semi-invasive diagnostic test for minimal to mild endometriosis. Hum Reprod 2009;24:3025 –3032. Brenner RM, Nayak NR, Slayden OD, Critchley HO, Kelly RW. Premenstrual and menstrual changes in the macaque and human endometrium: relevance to endometriosis. Ann N Y Acad Sci 2002;955:60–74; discussion 86 –68, 396 – 406. Bricou A, Batt RE, Chapron C. Peritoneal fluid flow influences anatomical distribution of endometriotic lesions: why Sampson seems to be right. Eur J Obstet Gynecol Reprod Biol 2008;138:127–134. Brosens I, Donnez J, Benagiano G. Improving the classification of endometriosis. Hum Reprod 1993;8:1792 –1795. Brouwer R, Woods RJ. Rectal endometriosis: results of radical excision and review of published work. ANZ J Surg 2007;77:562– 571. Bulletti C, Rossi S, Albonetti A, Polli VV, De Ziegler D, Massoneau M, Flamigni C. Uterine Contractility in Patients with Endometriosis. J Am Assoc Gynecol Laparosc 1996;3:S5. Bulletti C, De Ziegler D, Setti PL, Cicinelli E, Polli V, Flamigni C. The patterns of uterine contractility in normal menstruating women: from physiology to pathology. Ann N Y Acad Sci 2004;1034:64– 83. Bulletti C, Montini A, Setti PL, Palagiano A, Ubaldi F, Borini A. Vaginal parturition decreases recurrence of endometriosis. Fertil Steril. 2009. Bulun SE. Endometriosis. N Engl J Med 2009;360:268 –279. Bulun SE, Zeitoun K, Takayama K, Noble L, Michael D, Simpson E, Johns A, Putman M, Sasano H. Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis. Endocr Relat Cancer 1999; 6:293– 301. Burnstock G. Autonomic neurotransmission: 60 years since sir Henry Dale. Annu Rev Pharmacol Toxicol 2009;49:1 –30. Buscher U, Chen FC, Kentenich H, Schmiady H. Cytokines in the follicular fluid of stimulated and non-stimulated human ovaries; is ovulation a suppressed inflammatory reaction? Hum Reprod 1999;14:162 –166. Buyalos RP, Funari VA, Azziz R, Watson JM, Martinez-Maza O. Elevated interleukin-6 levels in peritoneal fluid of patients with pelvic pathology. Fertil Steril 1992; 58:302– 306. Calandre EP, Hidalgo J, Garcia-Leiva JM, Rico-Villademoros F. Trigger point evaluation in migraine patients: an indication of peripheral sensitization linked to migraine predisposition? Eur J Neurol 2006;13:244– 249. Carmeliet P, Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature 2005;436:193 –200. Cason AM, Samuelsen CL, Berkley KJ. Estrous changes in vaginal nociception in a rat model of endometriosis. Horm Behav 2003;44:123–131. Cervero F, Janig W. Visceral nociceptors: a new world order? Trends Neurosci 1992; 15:374– 378. Chalubinski K, Deutinger J, Bernaschek G. Vaginosonography for recording of cycle-related myometrial contractions. Fertil Steril 1993;59:225–228. Chapron C, Vercellini P, Barakat H, Vieira M, Dubuisson JB. Management of ovarian endometriomas. Hum Reprod Update 2002;8:591 –597. Chapron C, Fauconnier A, Dubuisson JB, Barakat H, Vieira M, Breart G. Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease. Hum Reprod 2003;18:760 –766.

342 Chapron C, Pietin-Vialle C, Borghese B, Davy C, Foulot H, Chopin N. Associated ovarian endometriomas is a marker for greater severity of deeply infiltrating endometriosis. Fertil Steril. 2008. Cheng JK, Ji RR. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res 2008;33:1970 – 1978. Cheong Y, Tay P, Luk F, Gan HC, Li TC, Cooke I. Laparoscopic surgery for endometriosis: How often do we need to re-operate? J Obstet Gynaecol 2008; 28:82 –85. Chopin N, Ballester M, Borghese B, Fauconnier A, Foulot H, Malartic C, Chapron C. Relation between severity of dysmenorrhea and endometrioma. Acta Obstet Gynecol Scand 2006;85:1375 –1380. Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993; 52:259– 285. Coelho A, Fioramonti J, Bueno L. Brain interleukin-1beta and tumor necrosis factor-alpha are involved in lipopolysaccharide-induced delayed rectal allodynia in awake rats. Brain Res Bull 2000;52:223– 228. Collins J, Crosignani PG. Endometrial bleeding. Hum Reprod Update 2007; 13:421– 431. Craft RM, Mogil JS, Aloisi AM. Sex differences in pain and analgesia: the role of gonadal hormones. Eur J Pain 2004;8:397–411. Cramer DW, Missmer SA. The epidemiology of endometriosis. Ann N Y Acad Sci 2002;955:11– 22; discussion 34– 16, 396 –406. Critchley HO, Kelly RW, Brenner RM, Baird DT. The endocrinology of menstruation –a role for the immune system. Clin Endocrinol (Oxf) 2001; 55:701– 710. Critchley HO, Kelly RW, Baird DT, Brenner RM. Regulation of human endometrial function: mechanisms relevant to uterine bleeding. Reprod Biol Endocrinol 2006; 4(Suppl 1):S5. Crofford LJ. The hypothalamic-pituitary-adrenal axis in the pathogenesis of rheumatic diseases. Endocrinol Metab Clin North Am 2002;31:1 – 13. Cumiskey J, Whyte P, Kelehan P, Gibbons D. A detailed morphologic and immunohistochemical comparison of pre- and postmenopausal endometriosis. J Clin Pathol 2008;61:455 –459. Daniels J, Gray R, Hills RK, Latthe P, Buckley L, Gupta J, Selman T, Adey E, Xiong T, Champaneria R et al. Laparoscopic uterosacral nerve ablation for alleviating chronic pelvic pain: a randomized controlled trial. J Am Med Assoc 2009; 302:955 –961. Davis LJ, Kennedy SS, Moore J, Prentice A. Oral contraceptives for pain associated with endometriosis. Cochrane Database Syst Rev 2007;(Issue 3):CD001019. DeLeo JA. Basic science of pain. J Bone Joint Surg Am 2006;88(Suppl. 2): 58 –62. DeSantana JM, Sluka KA. Central mechanisms in the maintenance of chronic widespread noninflammatory muscle pain. Curr Pain Headache Rep 2008; 12:338– 343. Dionne RA, Bartoshuk L, Mogil J, Witter J. Individual responder analyses for pain: does one pain scale fit all? Trends Pharmacol Sci 2005;26:125 –130. Divasta AD, Laufer MR, Gordon CM. Bone density in adolescents treated with a GnRH agonist and add-back therapy for endometriosis. J Pediatr Adolesc Gynecol 2007;20:293 –297. Dmitrieva N, Nikonov A, Berkley KJ. Endometriosis (ENDO) in the Rat: Sensitization of Afferent Fibers that Innervate the Ectopic Growths. Washington, DC: Society for Neuroscience, 2009. Dmitrieva N, Nagabukuro H, Resuehr D, Zhang G, McAllister SL, McGinty KA, Mackie K, Berkley KJ. Endocannabinoid involvement in endometriosis. Pain 2010; Epub ahead of print September 10. Dmowski WP, Rao R, Scommegna A. The luteinized unruptured follicle syndrome and endometriosis. Fertil Steril 1980;33:30 –34. Donnez J, Langerock S, Thomas K. Peritoneal fluid volume and 17 beta-estradiol and progesterone concentrations in ovulatory, anovulatory, and postmenopausal women. Obstet Gynecol 1982;59:687–692. Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, Kerns RD, Stucki G, Allen RR, Bellamy N et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9 – 19. Dworkin RH, O’Connor AB, Audette J, Baron R, Gourlay GK, Haanpaa ML, Kent JL, Krane EJ, Lebel AA, Levy RM et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010;85:S3 –14.

Stratton and Berkley

Evans S, Moalem-Taylor G, Tracey DJ. Pain and endometriosis. Pain 2007;132(Suppl 1):S22 –25. Evrard HC, Balthazart J. Aromatase (estrogen synthase) activity in the dorsal horn of the spinal cord: functional implications. Ann N Y Acad Sci 2003;1007:263– 271. Evrard HC, Balthazart J. Rapid regulation of pain by estrogens synthesized in spinal dorsal horn neurons. J Neurosci 2004;24:7225– 7229. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update 2005;11:595 –606. Fauconnier A, Chapron C, Dubuisson JB, Vieira M, Dousset B, Breart G. Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis. Fertil Steril 2002;78:719– 726. Fedele L, Bianchi S, Zanconato G, Bettoni G, Gotsch F. Long-term follow-up after conservative surgery for rectovaginal endometriosis. Am J Obstet Gynecol 2004; 190:1020 –1024. Fedele L, Somigliana E, Frontino G, Benaglia L, Vigano P. New drugs in development for the treatment of endometriosis. Expert Opin Investig Drugs 2008; 17:1187– 1202. Flower A, Liu JP, Chen S, Lewith G, Little P. Chinese herbal medicine for endometriosis. Cochrane Database Syst Rev 2009;(Issue 3):CD006568. Fraser IS, Tokushige N, Markham R, Russell P. Sensory nerve endings and endometriotic implants. Fertil Steril 2008;89:1847. Gambone JC, Mittman BS, Munro MG, Scialli AR, Winkel CA. Consensus statement for the management of chronic pelvic pain and endometriosis: proceedings of an expert-panel consensus process. Fertil Steril 2002;78:961– 972. Gao X, Outley J, Botteman M, Spalding J, Simon JA, Pashos CL. Economic burden of endometriosis. Fertil Steril 2006;86:1561 –1572. Gebhart GF. Peripheral contributions to visceral hyperalgesia. Can J Gastroenterol 1999;13(Suppl A):37A– 41A. Giamberardino MA, Valente R, Affaitati G, Vecchiet L. Central neuronal changes in recurrent visceral pain. Int J Clin Pharmacol Res 1997;17:63– 66. Giamberardino MA, De Laurentis S, Affaitati G, Lerza R, Lapenna D, Vecchiet L. Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women. Neurosci Lett 2001;304:61– 64. Giamberardino MA, Berkley KJ, Affaitati G, Lerza R, Centurione L, Lapenna D, Vecchiet L. Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats. Pain 2002; 95:247– 257. Giudice LC, Kao LC. Endometriosis. Lancet 2004;364:1789 –1799. Goodman HM, Kredentser D, Deligdisch L. Postmenopausal endometriosis associated with hormone replacement therapy. A case report. J Reprod Med 1989;34:231 –233. Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, Gold MS, Holdcroft A, Lautenbacher S, Mayer EA et al. Studying sex and gender differences in pain and analgesia: a consensus report. Pain 2007; 132(Suppl 1):S26– 45. Griep EN, Boersma JW, Lentjes EG, Prins AP, van der Korst JK, de Kloet ER. Function of the hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and low back pain. J Rheumatol 1998;25:1374– 1381. Grow DR, Iromloo K. Oral contraceptives maintain a very thin endometrium before operative hysteroscopy. Fertil Steril 2006;85:204 –207. Heitkemper M, Jarrett M. Overlapping conditions in women with irritable bowel syndrome. Urol Nurs 2005;25:25– 30; quiz 31 Holzer P. Neurogenic vasodilatation and plasma leakage in the skin. Gen Pharmacol 1998;30:5 – 11. Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obstet Gynecol Surv 1993;48:357– 387. Howard FM. The role of laparoscopy in the chronic pelvic pain patient. Clin Obstet Gynecol 2003;46:749– 766. Howard FM. Endometriosis and mechanisms of pelvic pain. J Minim Invasive Gynecol 2009;16:540 –550. Howard FM, El-Minawi AM, Sanchez RA. Conscious pain mapping by laparoscopy in women with chronic pelvic pain. Obstet Gynecol 2000;96:934– 939. Huang HY. Medical treatment of endometriosis. Chang Gung Med J 2008; 31:431– 440. Jabbour HN, Kelly RW, Fraser HM, Critchley HO. Endocrine regulation of menstruation. Endocr Rev 2006;27:17 –46.

Relationship between pain and endometriosis

Janig W, Levine JD, Michaelis M. Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma. Prog Brain Res 1996; 113:161 –184. Jarrell J. Myofascial dysfunction in the pelvis. Curr Pain Headache Rep 2004; 8:452– 456. Jarrell J, Mohindra R, Ross S, Taenzer P, Brant R. Laparoscopy and reported pain among patients with endometriosis. J Obstet Gynaecol Can 2005;27:477– 485. Jarrell J, Brant R, Leung W, Taenzer P. Women’s pain experience predicts future surgery for pain associated with endometriosis. J Obstet Gynaecol Can 2007; 29:988– 991. Jenkins TR, Liu CY, White J. Does response to hormonal therapy predict presence or absence of endometriosis? J Minim Invasive Gynecol 2008;15:82 –86. Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms. Trends Neurosci 2003a;26:696 –705. Ji Y, Murphy AZ, Traub RJ. Estrogen modulates the visceromotor reflex and responses of spinal dorsal horn neurons to colorectal stimulation in the rat. J Neurosci 2003b;23:3908 –3915. Ji Y, Tang B, Traub RJ. Modulatory effects of estrogen and progesterone on colorectal hyperalgesia in the rat. Pain 2005;117:433– 442. Jones CA, Li DY. Common cues regulate neural and vascular patterning. Curr Opin Genet Dev 2007;17:332– 336. Jones KD, Haines P, Sutton CJ. Long-term follow-up of a controlled trial of laser laparoscopy for pelvic pain. JSLS 2001;5:111 –115. Katsuki Y, Takano Y, Futamura Y, Shibutani Y, Aoki D, Udagawa Y, Nozawa S. Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats. Eur J Endocrinol 1998;138:216 –226. Kaur G, Janik J, Isaacson LG, Callahan P. Estrogen regulation of neurotrophin expression in sympathetic neurons and vascular targets. Brain Res 2007; 1139:6 – 14. Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, Greb R, Hummelshoj L, Prentice A, Saridogan E. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod 2005;20:2698 –2704. Kettel LM, Murphy AA, Morales AJ, Yen SS. Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486). Am J Obstet Gynecol 1998; 178:1151 – 1156. Kido A, Togashi K, Kataoka M, Maetani Y, Nakai A, Kataoka ML, Koyama T, Fujii S. The effect of oral contraceptives on uterine contractility and menstrual pain: an assessment with cine MR imaging. Hum Reprod 2007;22:2066 –2071. Kim-Bjorklund T, Landgren BM, Hamberger L. Peritoneal fluid volume and levels of steroid hormones and gonadotrophins in peritoneal fluid of normal and norethisterone-treated women. Hum Reprod 1991;6:1233 –1237. Koh CH, Janik GM. The surgical management of deep rectovaginal endometriosis. Curr Opin Obstet Gynecol 2002;14:357– 364. Komisaruk BR, Adler NT, Hutchison J. Genital sensory field: enlargement by estrogen treatment in female rats. Science 1972;178: 1295 – 1298. Koninckx PR, Meuleman C, Demeyere S, Lesaffre E, Cornillie FJ. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril 1991;55:759 –765. Koninckx PR, Oosterlynck D, D’Hooghe T, Meuleman C. Deeply infiltrating endometriosis is a disease whereas mild endometriosis could be considered a non-disease. Ann N Y Acad Sci 1994;734:333– 341. Koninckx PR, Kennedy SH, Barlow DH. Endometriotic disease: the role of peritoneal fluid. Hum Reprod Update 1998;4:741 –751. Koninckx PR, Craessaerts M, Timmerman D, Cornillie F, Kennedy S. Anti-TNF-alpha treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial. Hum Reprod 2008;23:2017– 2023. Kow LM, Pfaff DW. Effects of estrogen treatment on the size of receptive field and response threshold of pudendal nerve in the female rat. Neuroendocrinology 1973; 13:299– 313. Kristensen J, Kjer JJ. Laparoscopic laser resection of rectovaginal pouch and rectovaginal septum endometriosis: the impact on pelvic pain and quality of life. Acta Obstet Gynecol Scand 2007;86:1467 –1471. Kyama CM, Mihalyi A, Simsa P, Falconer H, Fulop V, Mwenda JM, Peeraer K, Tomassetti C, Meuleman C, D’Hooghe TM. Role of cytokines in the endometrial-peritoneal cross-talk and development of endometriosis. Front Biosci (Elite Ed) 2009;1:444 –454.

343 Laufer MR. Current approaches to optimizing the treatment of endometriosis in adolescents. Gynecol Obstet Invest 2008;66(Suppl. 1):19–27. Lentjes EG, Griep EN, Boersma JW, Romijn FP, de Kloet ER. Glucocorticoid receptors, fibromyalgia and low back pain. Psychoneuroendocrinology 1997; 22:603– 614. Leserman J, Zolnoun D, Meltzer-Brody S, Lamvu G, Steege JF. Identification of diagnostic subtypes of chronic pelvic pain and how subtypes differ in health status and trauma history. Am J Obstet Gynecol 2006;195:554– 560; discussion 560 –551. Leyendecker G, Kunz G, Wildt L, Beil D, Deininger H. Uterine hyperperistalsis and dysperistalsis as dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and infertility. Hum Reprod 1996;11:1542 –1551. Li J, Micevych P, McDonald J, Rapkin A, Chaban V. Inflammation in the uterus induces phosphorylated extracellular signal-regulated kinase and substance P immunoreactivity in dorsal root ganglia neurons innervating both uterus and colon in rats. J Neurosci Res 2008;86:2746 –2752. Ling FW. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Pelvic Pain Study Group. Obstet Gynecol 1999;93:51– 58. Lockhat FB, Emembolu JO, Konje JC. The evaluation of the effectiveness of an intrauterine-administered progestogen (levonorgestrel) in the symptomatic treatment of endometriosis and in the staging of the disease. Hum Reprod 2004;19:179 –184. Lockhat FB, Emembolu JO, Konje JC. The efficacy, side-effects and continuation rates in women with symptomatic endometriosis undergoing treatment with an intra-uterine administered progestogen (levonorgestrel): a 3 year follow-up. Hum Reprod 2005;20:789– 793. Lu KH, Hopper BR, Vargo TM, Yen SS. Chronological changes in sex steroid, gonadotropin and prolactin secretions in aging female rats displaying different reproductive states. Biol Reprod 1979;21:193–203. Lundeberg T, Lund I. Is there a role for acupuncture in endometriosis pain, or ‘endometrialgia’? Acupunct Med 2008;26:94 –110. Lv D, Song H, Shi G. Anti-TNF-alpha treatment for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2010;3:CD008088. Maier SF, Watkins LR. Immune-to-central nervous system communication and its role in modulating pain and cognition: Implications for cancer and cancer treatment. Brain Behav Immun 2003;17(Suppl 1):S125 – 131. Maier SF, Wiertelak EP, Martin D, Watkins LR. Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin. Brain Res 1993; 623:321 –324. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997;337:217– 222. Martin DC, Hubert GD, Vander Zwaag R, el-Zeky FA. Laparoscopic appearances of peritoneal endometriosis. Fertil Steril 1989;51:63–67. Martinez-Gaudio M, Yoshida T, Bengtsson LP. Propagated and nonpropagated myometrial contractions in normal menstrual cycles. Am J Obstet Gynecol 1973; 115:107 –111. Maslow KD, Lyons EA. Effect of prostaglandin and antiprostaglandin on midcycle myometrial contractions. Fertil Steril 2004;82:511 –513. May K, Becker CM. Endometriosis and angiogenesis. Minerva Ginecol 2008; 60:245– 254. Mayer D, Bushnell MC. Functional Pain Syndromes: Presentation and Pathophysiology. Seattle: IASP Press, 2009. McAllister SL, McGinty KA, Resuehr D, Berkley KJ. Endometriosis-induced vaginal hyperalgesia in the rat: role of the ectopic growths and their innervation. Pain 2009;147:255– 264. McGinty KA, Zhang G, McAllister SL, Herzog AJ, Crampton LJ, Dmitrieva N, Berkley KJ. Endometriosis (ENDO) and Co-morbidity with Bladder Dysfunction in the Rat: Influence of ENDO and shamENDO on Spinal c-Fos Expression Induced by Distention of the Uninflamed and Inflamed Bladder. Washington, DC: Society for Neuroscience, 2009. McMahon SB. Mechanisms of sympathetic pain. Br Med Bull 1991;47:584 –600. Mechsner S, Kaiser A, Kopf A, Gericke C, Ebert A, Bartley J. A pilot study to evaluate the clinical relevance of endometriosis-associated nerve fibers in peritoneal endometriotic lesions. Fertil Steril 2009;92: 1856 – 1861.

344 Melzack R, Coderre TJ, Katz J, Vaccarino AL. Central neuroplasticity and pathological pain. Ann N Y Acad Sci 2001;933:157– 174. Mendell LM, Albers KM, Davis BM. Neurotrophins, nociceptors, and pain. Microsc Res Tech 1999;45:252 –261. Mereu L, Ruffo G, Landi S, Barbieri F, Zaccoletti R, Fiaccavento A, Stepniewska A, Pontrelli G, Minelli L. Laparoscopic treatment of deep endometriosis with segmental colorectal resection: short-term morbidity. J Minim Invasive Gynecol 2007;14:463 –469. Merskey H, Bogduk N. Classification of Chronic Pain. Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, 2nd edn. Seattle, WA: IASP Press, 1994. Michaelis M, Habler HJ, Jaenig W. Silent afferents: a separate class of primary afferents? Clin Exp Pharmacol Physiol 1996;23:99 –105. Minici F, Tiberi F, Tropea A, Fiorella M, Orlando M, Gangale MF, Romani F, Catino S, Campo S, Lanzone A. et al. Paracrine regulation of endometriotic tissue. Gynecol Endocrinol 2007;23:574 –580. Mirkin D, Murphy-Barron C, Iwasaki K. Actuarial analysis of private payer administrative claims data for women with endometriosis. J Manag Care Pharm 2007;13:262 –272. Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Malspeis S, Willett WC, Hunter DJ. Reproductive history and endometriosis among premenopausal women. Obstet Gynecol 2004;104:965–974. Mohr C, Nezhat FR, Nezhat CH, Seidman DS, Nezhat CR. Fertility considerations in laparoscopic treatment of infiltrative bowel endometriosis. JSLS 2005;9:16– 24. Morrissey K, Idriss N, Nieman L, Winkel C, Stratton P. Dysmenorrhea after bilateral tubal ligation: a case of retrograde menstruation. Obstet Gynecol 2002; 100:1065 –1067. Morrison TC, Dmitrieva N, Winnard KP, Berkley KJ. Opposing viscerovisceral effects of surgically induced endometriosis and a control abdominal surgery on the rat bladder. Fertil Steril 2006;86:1067–1073. Nagabukuro H, Berkley KJ. Endometriosis-induced Vaginal Allodynia in the Rat: Alleviation Using Acute Delivery of WIN 55212 – 2 (WN2) Acting on CB1 Receptors. San Diego, CA: Society for Neuroscience, 2007a. Nagabukuro H, Berkley KJ. Influence of endometriosis on visceromotor and cardiovascular responses induced by vaginal distention in the rat. Pain 2007b; 132(Suppl 1):S96– 103. Nakamura M, Katsuki Y, Shibutani Y, Oikawa T. Dienogest, a synthetic steroid, suppresses both embryonic and tumor-cell-induced angiogenesis. Eur J Pharmacol 1999;386:33– 40. Nawroth F, Rahimi G, Nawroth C, Foth D, Ludwig M, Schmidt T. Is there an association between septate uterus and endometriosis? Hum Reprod 2006; 21:542– 544. Nayak NR, Critchley HO, Slayden OD, Menrad A, Chwalisz K, Baird DT, Brenner RM. Progesterone withdrawal up-regulates vascular endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque endometrium: potential relevance to menstruation. J Clin Endocrinol Metab 2000;85:3442 –3452. Nezhat C, Nezhat F, Pennington E. Laparoscopic treatment of infiltrative rectosigmoid colon and rectovaginal septum endometriosis by the technique of videolaparoscopy and the CO2 laser. Br J Obstet Gynaecol 1992;99:664– 667. Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997;68:585 –596. Nisolle-Pochet M, Casanas-Roux F, Donnez J. Histologic study of ovarian endometriosis after hormonal therapy. Fertil Steril 1988;49:423 –426. Oktem M, Esinler I, Eroglu D, Haberal N, Bayraktar N, Zeyneloglu HB. High-dose atorvastatin causes regression of endometriotic implants: a rat model. Hum Reprod 2007;22:1474 –1480. Olive DL, Henderson DY. Endometriosis and mullerian anomalies. Obstet Gynecol 1987;69:412 –415. Olive DL, Pritts EA. Treatment of endometriosis. N Engl J Med 2001;345:266– 275. Osteen KG, Bruner-Tran KL, Eisenberg E. Reduced progesterone action during endometrial maturation: a potential risk factor for the development of endometriosis. Fertil Steril 2005;83:529– 537. Ozawa Y, Murakami T, Terada Y, Yaegashi N, Okamura K, Kuriyama S, Tsuji I. Management of the pain associated with endometriosis: an update of the painful problems. Tohoku J Exp Med 2006;210:175 –188.

Stratton and Berkley

Parazzini F, Cipriani S, Moroni S, Crosignani PG. Relationship between stage, site and morphological characteristics of pelvic endometriosis and pain. Hum Reprod 2001; 16:2668– 2671. Parazzini F, Mais V, Cipriani S. Adhesions and pain in women with first diagnosis of endometriosis: results from a cross-sectional study. J Minim Invasive Gynecol 2006; 13:49 –54. Parker JD, Sinaii N, Segars JH, Godoy H, Winkel C, Stratton P. Adhesion formation after laparoscopic excision of endometriosis and lysis of adhesions. Fertil Steril 2005;84:1457 –1461. Parker JD, Leondires M, Sinaii N, Premkumar A, Nieman LK, Stratton P. Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis. Fertil Steril 2006;86:711– 715. Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa ESJC, Podgaec S, Bahamondes L. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20:1993 –1998. Possover M, Tersiev P, Angelov DN. Comparative study of the neuropeptide-Y sympathetic nerves in endometriotic involved and noninvolved sacrouterine ligaments in women with pelvic endometriosis. J Minim Invasive Gynecol 2009; 16:340– 343. Practice Committee of the American Society for Reproductive and Medicine. Treatment of pelvic pain associated with endometriosis. Fertil Steril 2008; 90:S260– 269. Prentice A, Deary AJ, Bland E. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database Syst Rev 2000a; (Issue 2):CD002122. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev 2000b; (Issue 2) CD000346. Pritts EA, Zhao D, Ricke E, Waite L, Taylor RN. PPAR-gamma decreases endometrial stromal cell transcription and translation of RANTES in vitro. J Clin Endocrinol Metab 2002;87:1841 –1844. Proctor M, Latthe P, Farquhar C, Khan K, Johnson N. Surgical interruption of pelvic nerve pathways for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev 2005;(Issue 4):CD001896. Quinn M, Armstrong G. Uterine nerve fibre proliferation in advanced endometriosis. J Obstet Gynaecol 2004;24:932 –933. Quinn MJ, Kirk N. Differences in uterine innervation at hysterectomy. Am J Obstet Gynecol 2002;187:1515– 1519; discussion 1519 – 1520. Raab S, Plate KH. Different networks, common growth factors: shared growth factors and receptors of the vascular and the nervous system. Acta Neuropathol 2007;113:607– 626. Ramer MS, Bisby MA. Adrenergic innervation of rat sensory ganglia following proximal or distal painful sciatic neuropathy: distinct mechanisms revealed by anti-NGF treatment. Eur J Neurosci 1999;11:837 –846. Rapkin AJ. Adhesions and pelvic pain: a retrospective study. Obstet Gynecol 1986; 68:13 –15. Redwine DB. Aggressive laparoscopic excision of endometriosis of the cul-de-sac and uterosacral ligaments. J Am Assoc Gynecol Laparosc 1997;4:540 –541. Redwine DB, Wright JT. Laparoscopic treatment of complete obliteration of the cul-de-sac associated with endometriosis: long-term follow-up of en bloc resection. Fertil Steril 2001;76:358– 365. Reed WR, Chadha HK, Hubscher CH. Effects of 17-{beta} estradiol on responses of viscerosomatic convergent thalamic neurons in the ovariectomized female rat. J Neurophysiol 2009;102:1062 –1074. Rees MC, Anderson AB, Demers LM, Turnbull AC. Endometrial and myometrial prostaglandin release during the menstrual cycle in relation to menstrual blood loss. J Clin Endocrinol Metab 1984a;58:813 –818. Rees MC, Anderson AB, Demers LM, Turnbull AC. Prostaglandins in menstrual fluid in menorrhagia and dysmenorrhoea. Br J Obstet Gynaecol 1984b;91:673– 680. Reich H, McGlynn F, Salvat J. Laparoscopic treatment of cul-de-sac obliteration secondary to retrocervical deep fibrotic endometriosis. J Reprod Med 1991; 36:516– 522. Ren K, Dubner R. Central nervous system plasticity and persistent pain. J Orofac Pain 1999;13:155 –163; discussion 164 – 171. Ren K, Dubner R. Pain facilitation and activity-dependent plasticity in pain modulatory circuitry: role of BDNF-TrkB signaling and NMDA receptors. Mol Neurobiol 2007;35:224– 235.

Relationship between pain and endometriosis

Ren K, Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity. Curr Opin Anaesthesiol 2008;21:570 –579. Romero LM, Sapolsky RM. Patterns of ACTH secretagog secretion in response to psychological stimuli. J Neuroendocrinol 1996;8:243– 258. Ryan IP, Taylor RN. Endometriosis and infertility: new concepts. Obstet Gynecol Surv 1997;52:365 –371. Safieh-Garabedian B, Dardenne M, Kanaan SA, Atweh SF, Jabbur SJ, Saade NE. The role of cytokines and prostaglandin-E(2) in thymulin induced hyperalgesia. Neuropharmacology 2000;39:1653 –1661. Salamanca A, Beltran E. Subendometrial contractility in menstrual phase visualized by transvaginal sonography in patients with endometriosis. Fertil Steril 1995; 64:193– 195. Salamonsen LA, Zhang J, Brasted M. Leukocyte networks and human endometrial remodelling. J Reprod Immunol 2002;57:95 –108. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol 1986;154:39–43. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 2000;21:55– 89. Schatman ME, Campbell A. (eds). Chronic Pain Management: Guidelines for Multidisciplinary Program Development. New York: Informal Healthcare USA, 2007. Scheenjes E, te Velde ER, Kremer J. Inspection of the ovaries and steroids in serum and peritoneal fluid at various time intervals after ovulation in fertile women: implications for the luteinized unruptured follicle syndrome. Fertil Steril 1990; 54:38–41. Scheenjes E, Thijssen JH, te Velde ER, Blankenstein MA, Kremer J. The origin of estrogens, progesterone, androgens and sex hormone binding globulin in peritoneal fluid in the immediate postovulatory period in normal ovulating women. Gynecol Endocrinol 1991;5: 157 –166. Schenken RS. Modern concepts of endometriosis. Classification and its consequences for therapy. J Reprod Med 1998;43:269– 275. Schulke L, Berbic M, Manconi F, Tokushige N, Markham R, Fraser IS. Dendritic cell populations in the eutopic and ectopic endometrium of women with endometriosis. Hum Reprod 2009;24:1695 –1703. Schweppe KW, Ring D. Peritoneal defects and the development of endometriosis in relation to the timing of endoscopic surgery during the menstrual cycle. Fertil Steril 2002;78:763 –766. Selak V, Farquhar C, Prentice A, Singla A. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2007;1:CD000068. Shakiba K, Bena JF, McGill KM, Minger J, Falcone T. Surgical treatment of endometriosis: a 7-year follow-up on the requirement for further surgery. Obstet Gynecol 2008;111:1285 –1292. Shaw RW. An open randomized comparative study of the effect of goserelin depot and danazol in the treatment of endometriosis. Zoladex Endometriosis Study Team. Fertil Steril 1992;58:265 –272. Sherrington CS. The Integrative Action of the Nervous System. New York: Schribner, 1906. Signorile PG, Campioni M, Vincenzi B, D’Avino A, Baldi A. Rectovaginal septum endometriosis: an immunohistochemical analysis of 62 cases. In Vivo 2009; 23:459– 464. Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update 2007;13:395–404. Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod 2002;17:2715 –2724. Sinaii N, Cleary SD, Younes N, Ballweg ML, Stratton P. Treatment utilization for endometriosis symptoms: a cross-sectional survey study of lifetime experience. Fertil Steril 2007;87:1277 –1286. Snider WD, McMahon SB. Tackling pain at the source: new ideas about nociceptors. Neuron 1998;20:629 –632. Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 2001;24:1217 –1281. Spechler S, Nieman LK, Premkumar A, Stratton P. The Keeper, a menstrual collection device, as a potential cause of endometriosis and adenomyosis. Gynecol Obstet Invest 2003;56:35– 37.

345 Spies JB, Coyne K, Guaou Guaou N, Boyle D, Skyrnarz-Murphy K, Gonzalves SM. The UFS-QOL, a new disease-specific symptom and health-related quality of life questionnaire for leiomyomata. Obstet Gynecol 2002;99:290– 300. Steege JF. Clinical utility of pelvic pain mapping. J Am Assoc Gynecol Laparosc 2001; 8:263– 266. Stegmann BJ, Gemmill J, Japp E, Chrousos G, Ballweg ML, Stratton P. Changes in the HPA Axis Associated with Chronic Pelvic Pain World Congress on Endometriosis. Melbourne, Australia. 2008a. Stegmann BJ, Sinaii N, Liu S, Segars J, Merino M, Nieman LK, Stratton P. Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women. Fertil Steril 2008b;89:1632– 1636. Stegmann BJ, Funk MJ, Sinaii N, Hartmann KE, Segars J, Nieman LK, Stratton P. A logistic model for the prediction of endometriosis. Fertil Steril 2009;91:51–55. Stratton P, Sinaii N, Segars J, Koziol D, Wesley R, Zimmer C, Winkel C, Nieman LK. Return of chronic pelvic pain from endometriosis after raloxifene treatment: a randomized controlled trial. Obstet Gynecol 2008;111:88– 96. Surrey ES. Add-back therapy and gonadotropin-releasing hormone agonists in the treatment of patients with endometriosis: can a consensus be reached? Add-Back Consensus Working Group. Fertil Steril 1999;71:420–424. Surrey ES, Hornstein MD. Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: long-term follow-up. Obstet Gynecol 2002; 99:709– 719. Sutton CJ, Ewen SP, Whitelaw N, Haines P. Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril 1994;62:696 –700. Sutton CJ, Pooley AS, Ewen SP, Haines P. Follow-up report on a randomized controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal to moderate endometriosis. Fertil Steril 1997;68:1070 –1074. Szolcsanyi J. Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides 2004;38:377– 384. Takayama K, Zeitoun K, Gunby RT, Sasano H, Carr BR, Bulun SE. Treatment of severe postmenopausal endometriosis with an aromatase inhibitor. Fertil Steril 1998;69:709 –713. Tamburro S, Canis M, Albuisson E, Dechelotte P, Darcha C, Mage G. Expression of transforming growth factor beta1 in nerve fibers is related to dysmenorrhea and laparoscopic appearance of endometriotic implants. Fertil Steril 2003;80:1131–1136. Tang B, Ji Y, Traub RJ. Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat. Pain 2008;137:540– 549. Taylor RN, Ryan IP, Moore ES, Hornung D, Shifren JL, Tseng JF. Angiogenesis and macrophage activation in endometriosis. Ann N Y Acad Sci 1997;828:194 –207. Taylor BK, Akana SF, Peterson MA, Dallman MF, Basbaum AI. Pituitary-adrenocortical responses to persistent noxious stimuli in the awake rat: endogenous corticosterone does not reduce nociception in the formalin test. Endocrinology 1998;139:2407– 2413. Tee MK, Vigne JL, Taylor RN. All-trans retinoic acid inhibits vascular endothelial growth factor expression in a cell model of neutrophil activation. Endocrinology 2006;147:1264 –1270. Theoharides TC. Treatment approaches for painful bladder syndrome/interstitial cystitis. Drugs 2007;67:215– 235. Tietjen GE, Bushnell CD, Herial NA, Utley C, White L, Hafeez F. Endometriosis is associated with prevalence of comorbid conditions in migraine. Headache 2007; 47:1069– 1078. Tokushige N, Markham R, Russell P, Fraser IS. High density of small nerve fibres in the functional layer of the endometrium in women with endometriosis. Hum Reprod 2006a;21:782– 787. Tokushige N, Markham R, Russell P, Fraser IS. Nerve fibres in peritoneal endometriosis. Hum Reprod 2006b;21:3001 –3007. Tokushige N, Markham R, Russell P, Fraser IS. Different types of small nerve fibers in eutopic endometrium and myometrium in women with endometriosis. Fertil Steril 2007;88:795 –803. Tokushige N, Markham R, Russell P, Fraser IS. Effects of hormonal treatment on nerve fibers in endometrium and myometrium in women with endometriosis. Fertil Steril 2008;90:1589 –1598. Torpy DJ, Papanicolaou DA, Lotsikas AJ, Wilder RL, Chrousos GP, Pillemer SR. Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: a pilot study in fibromyalgia. Arthritis Rheum 2000;43:872 –880.

346 Townson DH, Liptak AR. Chemokines in the corpus luteum: implications of leukocyte chemotaxis. Reprod Biol Endocrinol 2003;1:94. Treloar SA, Martin NG, Heath AC. Longitudinal genetic analysis of menstrual flow, pain, and limitation in a sample of Australian twins. Behav Genet 1998; 28:107– 116. Tulandi T, Chen MF, Al-Took S, Watkin K. A study of nerve fibers and histopathology of postsurgical, postinfectious, and endometriosis-related adhesions. Obstet Gynecol 1998;92:766–768. Tulandi T, Felemban A, Chen MF. Nerve fibers and histopathology of endometriosis-harboring peritoneum. J Am Assoc Gynecol Laparosc 2001;8:95– 98. Ugur M, Turan C, Mungan T, Kuscu E, Senoz S, Agis HT, Gokmen O. Endometriosis in association with mullerian anomalies. Gynecol Obstet Invest 1995;40:261–264. Varma R, Sinha D, Gupta JK. Non-contraceptive uses of levonorgestrel-releasing hormone system (LNG-IUS)—a systematic enquiry and overview. Eur J Obstet Gynecol Reprod Biol 2006;125:9 – 28. Vercellini P, Trespidi L, De Giorgi O, Cortesi I, Parazzini F, Crosignani PG. Endometriosis and pelvic pain: relation to disease stage and localization. Fertil Steril 1996;65:299 –304. Vercellini P, Aimi G, Panazza S, De Giorgi O, Pesole A, Crosignani PG. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril 1999;72:505 –508. Vercellini P, Fedele L, Pietropaolo G, Frontino G, Somigliana E, Crosignani PG. Progestogens for endometriosis: forward to the past. Hum Reprod Update 2003a;9:387 –396. Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003b;80:305– 309. Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani PG. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen. Fertil Steril 2003c; 80:560– 563. Vercellini P, Vigano P, Somigliana E. The role of the levonorgestrel-releasing intrauterine device in the management of symptomatic endometriosis. Curr Opin Obstet Gynecol 2005;17:359–365. Vercellini P, Fedele L, Aimi G, De Giorgi O, Consonni D, Crosignani PG. Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classification system. Hum Reprod 2006a;21:2679–2685. Vercellini P, Pietropaolo G, De Giorgi O, Daguati R, Pasin R, Crosignani PG. Reproductive performance in infertile women with rectovaginal endometriosis: is surgery worthwhile? Am J Obstet Gynecol 2006b;195:1303–1310. Vercellini P, Vigano P, Somigliana E, Daguati R, Abbiati A, Fedele L. Adenomyosis: epidemiological factors. Best Pract Res Clin Obstet Gynaecol 2006c;20:465– 477. Vercellini P, Fedele L, Aimi G, Pietropaolo G, Consonni D, Crosignani PG. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod 2007;22:266 –271. Vercellini P, Barbara G, Somigliana E, Bianchi S, Abbiati A, Fedele L. Comparison of contraceptive ring and patch for the treatment of symptomatic endometriosis. Fertil Steril 2009a. Vercellini P, Crosignani PG, Abbiati A, Somigliana E, Vigano P, Fedele L. The effect of surgery for symptomatic endometriosis: the other side of the story. Hum Reprod Update 2009b;15:177 –188. Vercellini P, Somigliana E, Vigano P, Abbiati A, Barbara G, Fedele L. Chronic pelvic pain in women: etiology, pathogenesis and diagnostic approach. Gynecol Endocrinol 2009c;25:149– 158. Vernon MW, Wilson EA. Studies on the surgical induction of endometriosis in the rat. Fertil Steril 1985;44:684–694. Vincent K, Kennedy S, Stratton P. Pain scoring in endometriosis: entry criteria and outcome measures for clinical trials. Report from the Art and Science of Endometriosis meeting. Fertil Steril 2008;1:1.

Stratton and Berkley

Waller KG, Shaw RW. Endometriosis, pelvic pain, and psychological functioning. Fertil Steril 1995;63:796 –800. Walters ET. Injury-related behavior and neuronal plasticity: an evolutionary perspective on sensitization, hyperalgesia, and analgesia. Int Rev Neurobiol 1994; 36:325– 427. Wang G, Tokushige N, Markham R, Fraser IS. Rich innervation of deep infiltrating endometriosis. Hum Reprod 2009;24:827 –834. Watkins LR, Maier SF, Goehler LE. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain 1995a;63:289 –302. Watkins LR, Maier SF, Goehler LE, Walters ET. Injury-related behaviour and neuronal plasticity: an evolutionary perspective on sensitization, hyperalgesia and analgesia. Int Rev Neurobiol 1995b;36:325 –327. Weinberg JB, Haney AF, Xu FJ, Ramakrishnan S. Peritoneal fluid and plasma levels of human macrophage colony-stimulating factor in relation to peritoneal fluid macrophage content. Blood 1991;78:513–516. Wheeler JM, Knittle JD, Miller JD. Depot leuprolide versus danazol in treatment of women with symptomatic endometriosis. I. Efficacy results. Am J Obstet Gynecol 1992;167:1367 –1371. Wieseler-Frank J, Maier SF, Watkins LR. Central proinflammatory cytokines and pain enhancement. Neurosignals 2005;14:166 –174. Wieser F, Cohen M, Gaeddert A, Yu J, Burks-Wicks C, Berga SL, Taylor RN. Evolution of medical treatment for endometriosis: back to the roots? Hum Reprod Update 2007;13:487 –499. Wieser F, Yu J, Park J, Gaeddert A, Cohen M, Vigne JL, Taylor RN. A botanical extract from channel flow inhibits cell proliferation, induces apoptosis, and suppresses CCL5 in human endometriotic stromal cells. Biol Reprod 2009; 81:371– 377. Winnard KP, Dmitrieva N, Berkley KJ. Cross-organ interactions between reproductive, gastrointestinal, and urinary tracts: modulation by estrous stage and involvement of the hypogastric nerve. Am J Physiol Regul Integr Comp Physiol 2006;291:R1592 –1601. Witz CA, Dechaud H, Montoya-Rodriguez IA, Thomas MR, Nair AS, Centonze VE, Schenken RS. An in vitro model to study the pathogenesis of the early endometriosis lesion. Ann N Y Acad Sci 2002;955:296– 307; discussion 340 – 292, 396 – 406 Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature 1983;306:686 –688. Woolf CJ. Phenotypic modification of primary sensory neurons: the role of nerve growth factor in the production of persistent pain. Philos Trans R Soc Lond B Biol Sci 1996;351:441 –448. Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004;140:441– 451. Woolf CJ, Ma Q. Nociceptors—noxious stimulus detectors. Neuron 2007; 55:353– 364. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288:1765 –1769. Wray S, Noble K. Sex hormones and excitation-contraction coupling in the uterus: the effects of oestrous and hormones. J Neuroendocrinol 2008;20:451 –461. Wright S, Valdes CT, Dunn RC, Franklin RR. Short-term Lupron or danazol therapy for pelvic endometriosis. Fertil Steril 1995;63: 504 –507. Yeung PP Jr., Shwayder J, Pasic RP. Laparoscopic management of endometriosis: comprehensive review of best evidence. J Minim Invasive Gynecol 2009; 16:269– 281. Zhang G, Dmitrieva N, Liu Y, McGinty KA, Berkley KJ. Endometriosis as a neurovascular condition: estrous variations in innervation, vascularization, and growth factor content of ectopic endometrial cysts in the rat. Am J Physiol Regul Integr Comp Physiol 2008;294:R162–171. Zhang X, Lu B, Huang X, Xu H, Zhou C, Lin J. Endometrial nerve fibers in women with endometriosis, adenomyosis, and uterine fibroids. Fertil Steril 2009; 92:1799– 1801.